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CAS No. : | 5111-70-6 | MDL No. : | MFCD00003789 |
Formula : | C10H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QOPRWBRNMPANKN-UHFFFAOYSA-N |
M.W : | 162.19 | Pubchem ID : | 78787 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.98 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 1.64 |
Log Po/w (WLOGP) : | 1.82 |
Log Po/w (MLOGP) : | 1.35 |
Log Po/w (SILICOS-IT) : | 2.74 |
Consensus Log Po/w : | 1.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.18 |
Solubility : | 1.06 mg/ml ; 0.00657 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.81 |
Solubility : | 2.54 mg/ml ; 0.0157 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.0948 mg/ml ; 0.000585 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.56 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H311-H331 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium azide; sulfuric acid In benzene at 0 - 60℃; for 24 h; | Sulfuric acid (82.6 mL) was carefully added, at 0° C., to 5-methoxy-1-indanone (25 g, 154 mmol) in benzene (400 mL) followed by sodium azide (18 g, 277.4 mmol). The resulting mixture was heated at 60° C. for 24 h. After cooling at room temperature, the benzene was evaporated and the resulting mixture was diluted with water and extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation the product was obtained as a white solid after purification by chromatography (SiO2, ethyl acetate/n-hexane 1:1 to 4:1 v:v gradient) (13.2 g, 49percent). MS: m/e=177.2 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With manganese(IV) oxide; ammonium hydroxide; oxygen; chlorobenzene In N,N-dimethyl-formamide at 100℃; for 24 h; Autoclave; Green chemistry | General procedure: 0.01g of MnO2 catalyst, 0.5mmol of 1-indanone, 0.2g of ammonia water (25wtpercent) and 2g of chlorobenzene were added to a stainless steel autoclave with a polytetrafluoroethylene inner liner.The temperature was raised to 110 by automatic temperature controller, 0.6MPa oxygen was added and the reaction was continued for 4h. The pressure was kept constant during the reaction.The reaction product was analyzed using GC-MS with a phthalamide yield of 85percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2.5 h; Reflux Stage #2: With triethylamine In tetrachloromethane at 0℃; |
General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol). The resulting mixture was stirred at reflux temperature for 2.5 h, then cooled and filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 °C and treated with triethylamine (0.28 mL, 2.0 mmol) overnight, then concentrated in vacuuo. Chromatography of the residue (1 : 9~1 : 4 EtOAc/hexanes) afforded 97 mg (60percent) of enone 1a as the pink oil which solidified as light red solid in refrigerator. |
70% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2.5 h; Reflux | General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol).The resulting mixture was stirred at reflux temperature for 2.5 h, then cooledand filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 °C and treated with triethylamine (0.28 mL, 2.0 mmol)overnight, then concentrated in vacuuo. Chromatography of the residue (19~14 EtOAc/hexanes) afforded 97 mg (60percent) of enone 1a as the pink oil which solidified as light red solid in refrigerator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bromine In ethyl acetate at 10 - 20℃; for 0.5h; | 2.1 Synthesis of Intermediate 22 At room temperature, dissolved in 81.1g compound 21 (0.5mol) 500ml of ethyl acetate, kept below 10 , was slowly added dropwise bromine 80g (0.5mol), Bi drops to keep stirring was continued at 20 30 Fenzhong, TLC monitoring until complete reaction, 1000ml water was added dropwise to quench the layers were separated and the organic phase was washed with saturated brine once 1000ml, dried over anhydrous sodium sulfate and concentrated to dryness to give a yellow oily liquid 120.54g (yield 99%), i.e. intermediate 22. |
87% | With N-Bromosuccinimide; toluene-4-sulfonic acid at 60℃; for 0.166667h; | |
With diethyl ether; bromine |
With tetra-N-butylammonium tribromide In methanol; dichloromethane at 20℃; | ||
With N-Bromosuccinimide; toluene-4-sulfonic acid at 80℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydroxylamine hydrochloride; sodium acetate In methanol at 22℃; for 16h; | B; 2102.B A mixture of intermediate from Step A above (44.7 mg), NH2OH.HCl (21 mg), and NaOAc (25 mg) in MeOH (1 mL) was allowed to stir for 16 h at 22° C. Water (5 mL) was added and the resulting precipitate was filtered and washed three times with water (1 mL) to afford the intermediate as a colourless solid (44 mg; 97%). [MH]+=178. |
With hydroxylamine hydrochloride; sodium acetate In tetrahydrofuran; methanol; water at 70℃; for 1.5h; | 22.2a 5-methoxy-2,3-dihydro-1H-inden-1-amine 5-Methoxy-2,3-dihydroinden-1-one (1 g, 6.17 mmol) was added to a solution of hydroxylamine HCl (730 mg, 10.5 mmol) in 10 ml of water. The mixture was brought up to 70° C. and a solution of sodium acetate (1.4 g, 16.7 mmol) in 7 mL of H2O, 14 ml of MeOH, 3 ml of THF was added. After stirring for 1.5 h at 70° C., 10 ml of H2O was added to produce a precipitate and the suspension was allowed to stir for 2 h. The precipitate was collected by filtration to give 5-methoxy-2,3-dihydroinden-1-one oxime almost quantitatively and was used in the next step without further purification. The oxime (0.5 g, 2.82 mmol) was dissolved in MeOH and a catalytic amount of Raney nickel and 25 mL of ammonia solution in MeOH (7N) was added. The reaction was stirred at r.t. overnight under H2. The slurry was filtered over celite and concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude title amine (yield, 45%). The crude amine was used without further purification. | |
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 4h; Reflux; | 9 Preparation of 5-methoxy-l-indanone oxime. To a mixture of 5-methoxy-l- indanone (1.0 g, 6.5 mmol) and hydroxylamine hydrochloride (1.1 g, 16 mmol) inethanol/water (30 mL/5 mL) was added sodium acetate (1.3 g, 16 mmol). After refluxing for 4 hrs, the reaction mixture was poured into water and the product was isolated by filtration to give a white solid (1.1 g, quantitative): (stereoisomers) MS m/z 178.3 (M+1). |
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 4h; Reflux; Inert atmosphere; | 70 To a suspension of compound SP-0010529-138 (1.9 g of the crude) in EtOH/H20(10 mL / 4.0 mL) were added a solution of hydroxylamine hydrochloride (1.72 g, 25 mmol)in EtOH/H20 (10 mL / 4.0 mL) and sodium acetate (2.05 g, 25.0 mmol). The mixture wasrefluxed for 4.0 h under N2 atmosphere. The reaction mixture was poured into water (100mL). The suspension was filtered off and the cake was the crude compound SP-0010529-139 as a brown solid (1.8 g of the crude). LC-MS 178 (M+H), purity 73% (UV 214 nm); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With Eaton?s reagent; at 20℃; for 72h; | Eaton's reagent (43 mL, 3 g/mmol of carboxylic acid 10) was added to carboxylic acid 10 (3.95 g, 21.9 mmol), and the reaction mixture was stirred at room temperature for 72 h. It was then poured over ice, neutralized, and extracted with EtOAc (3×50 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography using a prepacked 100 g silica column [solvent A: EtOAc; solvent B: hexane; gradient: 12% A/88% B (1 CV), 12% A/88% B?100% A/0% B (10 CV), 100% A/0% B (10 CV); flow rate: 50 mL/min; monitored at 254 nm and 280 nm] to afford ketone 12 (2.26 g, 13.9 mmol, 64%) as a green solid. 1H NMR (CDCl3, 600 MHz) delta 7.49 (1H, d, J=7.5 Hz), 6.72 (2H, m), 3.72 (3H, s), 2.91 (2H, t, J=6 Hz), 2.48 (2H, t, J=5.5 Hz). 13C NMR (CDCl3, 150 MHz) delta 205.0, 165.1, 158.1, 130.2, 125.0, 115.2, 109.6, 55.5, 36.3, 25.7. |
In PPA; Petroleum ether; benzene; | Preparation 1 1-Oxo-5-Methoxyindane A mixture of 5 g of 3-(3-methoxyphenyl)propionic acid in polyphosphoric acid was prepared. The mixture was heated for 2 hours at 120C. The mixture was cooled and ice was added. The resulting solid was removed by filtration and dissolved in benzene. The benzene solution was filtered and concentrated to one-fourth its original volume. Petroleum ether was added and the mixture was cooled to 5C. The product was collected by filtration. mp: 105C-107C. EA: Calc. for C10H10O2: C, 74.06; H, 6.22; O, 19.73. Found: C, 74.32; H, 6.42; O, 20.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium permanganate; copper(II) sulfate for 70h; Ambient temperature; | |
87% | With chromium(VI) oxide In water; acetic acid for 4.5h; Ambient temperature; | |
82% | With Bromotrichloromethane; Ir[2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine]<SUB>2</SUB>(4,4'-di-tert-butyl-2,2'-bipyridine)PF<SUB>6</SUB>; water; potassium carbonate In acetonitrile at 20℃; Irradiation; Inert atmosphere; regioselective reaction; |
68% | With chromium(VI) oxide In water; acetic acid; propionic acid 1) 5 - 10 deg C, 1 h 2) room temperature; | |
50% | With tetra-O-acetyl riboflavin; ferrous perchlorate; oxygen In water; acetonitrile at 50℃; for 0.416667h; UV-irradiation; Flow reactor; | |
With chromium(VI) oxide; acetic acid | ||
With chromium(VI) oxide; acetic acid | ||
With chromium(VI) oxide; acetic acid In water at 20℃; for 4.5h; Cooling with ice; | II Chromium(VI) oxide (2.90 g; 29.00 mmol; 1.95 eq.) in 80% aqueous acetic acid (20.00 ml) was added slowly to an ice-cold stirred solution of 2 (2.20 g; 14.84 mmol; 1.00 eq.) in acetic acid (30.00 ml) (reaction mixture colored black).The mixture was warmed to room temperature and stirred for 4.5 h. The solution was then extracted with dichloromethane, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo. 1.79 g of a beige solid containing 3 were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tetrahydroborate; water In tetrahydrofuran at 20℃; for 2h; | I Synthesis of Compounds 43-44 To a solution of Compound 43a (5-methoxy-2,3-dihydro-lH-inden-l-one) (1.50 g, 9.25 mmol) in THF/water (25 mL, 4:1) was added NaBLft (0.35 g, 9.25 mmol) at 0°C. After addition, the reaction mixture was slowly warmed to RT and stirred for 2 hrs.[0463] After reaction was completed, the reaction mixture was quenched with Sat. NH4CI. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with sat. NH4CI. The organic phase was dried with MgSC>4 and concentrated under reduced pressure to obtain the desired product Compound 43b (5-methoxy-2,3-dihydro-lH-inden-l-ol) (1.44 g, 8.81 mmol, yield 95%). The crude product was used in the next step without further purification. |
90% | With methanol; sodium tetrahydroborate at 20 - 25℃; for 2h; | 86.2 5-methoxy-2,3-dihydro- 1 H-inden- 1 -ol NaBH4 (93 mg, 2.46 mmol) was added to a methanolic solution of 5-methoxy-2,3- dihydro-1H-inden-1-one (Compound of step 1, 200 mg, 1.23 mmol) and the reaction mixture was stirred for 2 h at RT. After completion of reaction, methanol was evaporated and the solid obtained was dissolved in ethyl acetate and washed with water. Organic layer was collected and dried over Na2SO4 and solvent was evaporated obtain the title compound (182 mg). Yield: 90%. 1H NMR (CDC13, 300 MHz): 7.32-7.35 (m, 1H), 6.80 (brs, 2H), 5.20-5.22 (m, 1H), 3.82 (s, 3H), 3.02-3.12 (m, 1H), 2.75-2.86 (m, 1H), 2.46-2.53 (m, 1H), 1.95-2.04 (m, 1H). |
With sodium tetrahydroborate In ethanol |
With lithium aluminium tetrahydride In diethyl ether | ||
With potassium borohydride In methanol Yield given; | ||
With sodium tetrahydroborate In methanol for 2h; Heating; | ||
With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; | ||
With methanol; sodium tetrahydroborate for 2h; Reflux; | II To a mixture of 5-methoxy-1-indanone 3 (7.70 g; 47.48 mmol; 1.00 eq.) in methanol (200.00 ml) sodium borohydride (3.90 g; 103.09 mmol; 2.17 eq.) was added, and the mixture was refluxed for 2 h. Most of the methanol was removed using a rotoevaporator, and 75 ml of water was added. This mixture was extracted twice with ethyl acetate (total 225 ml). The ethyl acetate extracts were combined, dried over magnesium sulfate, and the solvent was removed at aspirator pressure to yield 6.3 g of a brown oil containing the corresponding alcohol of 3. | |
With sodium tetrahydroborate In methanol; dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; | ||
With methanol; sodium tetrahydroborate for 2h; Inert atmosphere; Sealed tube; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium <i>tert</i>-butylate; sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
96% | With potassium <i>tert</i>-butylate; sodium hydride In mineral oil at 0 - 20℃; Inert atmosphere; | |
85% | With sodium hydride In benzene for 5h; Reflux; |
77% | With sodium hydride at 80℃; | |
62% | With sodium hydride In benzene for 5h; Heating; | |
With sodium hydride | ||
With sodium hydride | ||
With sodium hydride In mineral oil at 100℃; | ||
With potassium <i>tert</i>-butylate In tetrahydrofuran; ethanol Reflux; | ||
With sodium hydride In tetrahydrofuran; mineral oil Inert atmosphere; Reflux; | Preparation of cyclic β-ketoesters General procedure: A solution of ketone (1.0 equiv) in THF (1 L/mol ketone) was added dropwise to a stirred solution of dialkyl carbonate (5.0-10 equiv.) in THF (2L/mol. ketone) containing NaH (60% dispersion in mineral oil, 2.1 equiv) under a nitrogen atmosphere. The mixture was heated to reflux (30 min to 16h) and cooled in an ice-bath and then acidified with 1mol/L hydrochloric acid (1.5L/mol, ketone). The residue was then extracted with Et2O (3x5L/mol, ketone). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography to give the β-ketoester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | AlCl3; In benzene; | The starting material was prepared as follows: To a solution of 5-methoxy-1-indanone (2 g, 12.3 mmol) in benzene (50 ml) was added AlCl3 (4 g, 31 mmol). The mixture was heated at reflux for 5 hours and extracted with ethyl acetate. The organic phase was evaporated and purified by flash chromatography, eluding with CH2 Cl2 /CH3 CN (90/10) to give 5-hydroxy-1-indanone as a yellow solid (1.65 g; 90%). 1 H-NMR (DMSO-d6): delta 2.58-2.67 (m, 2H); 2.94-3.01 (m, 2H); 6.79 (dd, 1H), 6.84 (s, 1H); 7.4.7 (d, 1H). |
90% | AlCl3; In benzene; | The starting material was prepared as follows: To a solution of 5-methoxy-1-indanone (2 g, 12.3 mmol) in benzene (50 ml) was added AlCl3 (4 g, 31 mmol). The mixture was heated at reflux for 5 hours and extracted with ethyl acetate. The organic phase was evaporated and purified by flash chromatography, eluding with CH2Cl2/CH3CN (90/10) to give 5-hydroxy-1-indanone as a yellow solid (1.65 g; 90%). 1H-NMR (DMSO-d6): delta 2.58-2.67 (m, 2H); 2.94-3.01 (m, 2H); 6.79 (dd, 1H), 6.84 (s, 1H); 7.47 (d, 1H). |
90% | With aluminum (III) chloride; In toluene; for 4h;Reflux; | Step 1. To a solution of 5-methoxy-indanone (10 g) dissolved in toluene (150 mL) was added AICI3 (15 g). The mixture was refluxed for 4 hours until a precipitate appeared. The resulting mixture was cooled and poured into ice water (150 mL). The precipitate was filtered and washed with water, then air-dried to give the desired product (8.5 g, 90%). |
90% | With aluminum (III) chloride; In toluene; for 4h;Reflux; | To a solution of 5-methoxy-indanone (10 g) dissolved in toluene (150 mL) was added AlCl3 (15 g). The mixture was refluxed for 4 hours until a precipitate appeared. The resulting mixture was cooled and poured into ice water (150 mL). The precipitate was filtered and washed with water, then air-dried to give the desired product (8.5 g, 90%). |
90% | With aluminum (III) chloride; In toluene; for 4h;Reflux; | To a solution of 5-methoxy-indanone (10 g) dissolved in toluene (150 mE) was added A1C13 (15 g). Themixture was refluxed for 4 hours until a precipitate appeared.The resulting mixture was cooled and poured into ice water(150 mE). The precipitate was filtered and washed withwater, then air-dried to give the desired product (8.5 g, 90%). |
60% | With hydrogen bromide; acetic acid; In water; at 110℃; for 2h;Inert atmosphere; | 4.6 5-Hydroxy-2,3-dihydro-1H-inden-1-one 6 5-Methoxy-2,3-dihydro-1H-inden-1-one (1.0 g) in glacial acetic acid (20 mL) was flushed with nitrogen, heated until it became homogeneous and then diluted with 48% HBr in H2O (80 mL). The mixture was heated at reflux (110 C) for 2 h, to give 5-hydroxy-2,3-dihydro-1H-inden-1-one in 60% yield. IR (KBr, v cm-1): 3435, 2925, 1694, 1601, 1492, 1307, 1253, 1095, 1037, 841; 1H NMR (300 MHz, CDCl3): delta 9.08 (s,1H, OH), 7.48 (t, 1H, Ar-H, J = 7.9, 7.7 HZ), 6.95 (d, 1H, Ar-H, J = 7.5 Hz), 6.77 (d, 1H, Ar-H, J = 8.3 Hz), 3.12 (t, 2H, CH2, J = 5.8, 5.2 Hz), 2.72 (t, 2H, CH2, J = 5.8, 5.4 Hz). 13C NMR (75 MHz, CDCl3+DMSO-d6): delta 204, 163.1, 157.4, 128, 124.3, 115.1, 111.3, 35.4, 24.6. MS (ESI): m/z =149 (M+H)+; HRMS: Calcd for C9H9O2: 149.05945. Found: 149.05971. |
With hydrogenchloride; In aluminum tri-bromide; dichloromethane; | EXAMPLE 13 5-Hydroxy-1-indanone To a solution of 17.4 g of 5methoxy-1-indanone in 650 ml of dry methylene chloride subject to mechanical stirring 100 g in portions of aluminum bromide are added. After 1 hour at room temperature, the mixture is refluxed for 24 hours and then cooled; thereafter, it is poured onto a mixture containing 260 g of ice and 150 ml of 6N hydrochloric acid under stirring. After 30 minutes, the insoluble is filtered off, washed with water till neutrality and dried, 14.11 g (89%) of a yellow solid chromatographically pure are obtained with M.P. 181-184 C. and elemental analysis correct. IR Spectrum (KBr), cm-1: 3440, 3100-2900, 1660, 1570, 1300, 1240, 1100, 805. 1 H-NMR (d6 -DMSO), ppm: 2.50 (m, 2H, --CH2 --CO--), 2.95 (m, 2H; Ar--CH2 --), 6.75 (m, 2H; Ar--), 7.47 (d, 1H, J=9 Hz; Ar--), and 10.40 (wide, 1H; --OH). | |
With boron tribromide; In dichloromethane; | To a mixture of 5-methoxyindan-l-one (200 g, 1.235 mol) in 2 L of anhydrous dichloromethane was added BBr3 (234 mL, 2.469 mol) slowly at -780C. The mixture was warmed slowly to rt and stirred overnight. Then the mixture was poured slowly into ice-water (2 L) with vigorously stirring for 30 min. The result mixture was filtered to give a solid. The filtrate was separated, and the aqueous phase was extracted with EtOAc (2 x 500 mL). The combined organic phases were washed with brine (1 L) and dried over Na2SO4 and concentrated to dryness to obtain another batch of solid. The combined solids were dried in vacuo to give the title compound. 1H-NMR (400 MHz, MeOD): delta 7.55 (d, J=8.1 Hz, IH), 6.78-6.84 (m, 2H), 3.03-3.06 (m, 2H), 2.60-2.63 (m, 2H) ppm. | |
Step A. 5-Hydroxyindan-l-one. To a mixture of 5-methoxyindan-l-one (200 g, 1.235 mol) in 2 L of anhydrous dichloromethane was added BBr3 (234 mL, 2.469 mol) slowly at -78C. The mixture was warmed slowly to rt and stirred overnight. Then the mixture was poured slowly into ice-water (2 L) with vigorous stirring for 30 min. The result mixture was filtered to give a solid. The filtrate was separated, and the aqueous phase was extracted with EtOAc (2 x 500 mL). The combined organic phases were washed with brine (1 L) and dried over Na2S04 and concentrated to dryness to obtain another batch of solid. The combined solids were dried in vacuo to give the title compound. -NMR (400 MHz, MeOD): delta 7.55 (d, J=8.1 Hz, 1H), 6.78-6.84 (m, 2H), 3.03-3.06 (m, 2H), 2.60-2.63 (m, 2H) ppm. | ||
In Concentrated HBr; acetic acid; | A. 5-Hydroxy-indan-1 -one A solution of 5-methoxy-indan-1-one (4.9 grams, 30 mmol)in 1:1 concentrated HBr/HOAc (150 mL) was heated at 112 C. for 28 hours. The reaction was cooled to 23 C. and filtered through celite. The filtrate was diluted with ethyl acetate (1000 mL) and washed with saturated aqueous NaCl (100 mL), saturated aqueous NaHCO3 (2*100 mL) and with saturated aqueous NaCl (100 mL). The ethyl acetate solution was dried (MgSO4) and concentrated in vacuo to give 1.6 grams of crude product. 1 H NMR (250 MHz, d6 -DMSO): d 7.45 (d, 1 H), 6.82 (s, 1 H), 6.78 (d, 1 H), 2.95 (t, 2H), 2.55 (t, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride; isopentyl nitrite In methanol at 50℃; for 0.5h; | |
85% | With hydrogenchloride; n-Butyl nitrite In methanol at 40℃; for 0.5h; | |
73% | With hydrogenchloride; isopentyl nitrite In methanol; water at 20 - 45℃; for 1h; | General synthetic procedures and characteristic data General procedure: A. General synthetic procedure for the synthesis of oxime derivatives 2, 7b-13b, and 15: To solution of 1-indanone (1, 1.32 g, 10 mmol for synthesis of 2), 3,3-dimethyl-2-indanone (7a, 1.60 g, 10 mmol for synthesis of 7b), 4-methyl-2-indanone (8a, 1.46 g, 10 mmol for synthesis of 8b), 5-methoxy-2-indanone (9a, 1.62 g, 10 mmol for synthesis of 9b), 6-methoxy-2-indanone (10a, 1.62 g, 10 mmol for synthesis of 10b), 5,6-dimethoxy-2-indanone (11a, 1.92 g, 10 mmol for synthesis of 11b), 4,5,6-trimethoxy-2-indanone (12a, 2.22 g, 10 mmol for synthesis of 12b), or 5,6-difluoro-2-indanone (13a, 1.68 g, 10 mmol for synthesis of 13b), and 2-indanone (14, 1.32 g, 10 mmol for synthesis of 15) in methanol (30 mL) was added isoamyl nitrite (1.52 g, 13 mmol) and conc. HCl (1.3 mL) at room temperature. The reaction mixture was stirred for 1-3 h at 45°C and concentrated under reduced pressure to remove the methanol. The residue was diluted with H2O, repeatedly extracted with dichloromethane (3 x 30 mL or 3 x 40 mL) and the combined extract was dried with anhydrous MgSO4 and filtered. The filtrate was evaporated to give the crude product under reduced pressure. The crude product was purified by short column chromatography using ethyl acetate/n-hexane (1:1) or recrystallized with methanol and n-hexane to obtain pure oxime derivatives 2, 7b-13b, and 15. |
70% | With hydrogenchloride; n-Butyl nitrite In methanol at 45℃; | |
With isopentyl nitrite | ||
With hydrogenchloride; ethyl nitrite In tetrahydrofuran; ethanol | ||
With hydrogenchloride; n-Butyl nitrite In diethyl ether | ||
With hydrogenchloride; isopentyl nitrite 1.) ether, 2.) ether,; Yield given. Multistep reaction; | ||
With hydrogenchloride; n-Butyl nitrite 1.) methanol, 40 deg C; 2.) methanol, 40 deg C, 0.5 h; Yield given. Multistep reaction; | ||
With hydrogenchloride; isopentyl nitrite In methanol; water at 45℃; for 1h; | General Procedure F for the Synthesis of Fluoroethyl Substituted Indan Ureas Isoamyl nitrite (1.1 eq) was added to a solution of a substituted indanone in MeOH at 45° C., followed by 2 mL of concentrated HCl. The resulting mixture was stirred for 1 hour, then was cooled to room temperature. The precipitate formed was filtered, washed with small amount of MeOH, then Et2O and dried under vacuum to give the desired oxime.xxii,xxiii. The crude oxime was dissolved in HOAc and H2SO4 was added slowly. The resulting mixture was purged with N2 and Pd/C (10%) was added. The reaction mixture was hydrogenated at 50 psi overnight. The catalyst was filtered through celite and the filtrate was concentrated. The concentrate was basified slowly using solid NaOH. The resulting solution was extracted with CH2Cl2 (3×75 mL) and the combined organic extracts were washed with H2O (2×25 mL), brine (1×25 mL), dried over K2CO3 and concentrated to give the desired indan-2-ylamine. This indan-2-ylamine was converted to the title urea using the chemistry described in general procedure A above. This method may be adapted to other cycloalkyl-aryl fused rings systems using starting materials such as those shown below.Synthesis of 1-(2-fluoro-ethyl)-3-(5-methoxy-indan-2-yl)-ureaThe title compound was generated from commercially available 5-methoxy-1-indanone according to the general procedure F described above. The intermediates 5-methoxy-indan-1,2-dione 2-oxime and 5-methoxy-indan-2-ylamine were isolated and characterized.5-Methoxy-indan-1,2-dione 2-oxime24: The title oxime was obtained from isoamyl nitrite (2.70 mL, 20.09 mmol) and 5-methoxy-1-indanone (3.00 g, 18.50 mmol) according to general procedure F described above. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 3.7 (s, 2H), 3.9 (s, 3H), 6.99-7.04 (m, 1H), 7.1 (s, 1H), 7.7 (d, 1H, J=8.5 Hz), 12.5 (s, 1H). | |
With hydrogenchloride; isopentyl nitrite In methanol; water at 40℃; for 1h; | ||
Stage #1: 5-methoxy-1-indanone With potassium <i>tert</i>-butylate In diethyl ether at 0℃; for 0.5h; Stage #2: With tert.-butylnitrite In diethyl ether for 1h; | 92 To a solution of 5-hydroxy-2,3-dihydroinden-1-one (1.48 g, 10.0 mmol) in dry DMF (20 mL) were added iodomethane (7.1 g, 50.0 mmol) and K2C03 (2.76 g, 20.0 mmol). The mixture was stirred at room temperature for 20 h under N2 atmosphere. The resulting mixture was quenched with water (100 mL), extracted with EtOAc (2 x 100 mL) and washed with brine (50 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated to give the crude product SP-0010529-138 as a brown solid (1.9 g of the crude). LC-MS 163 (M+H), purity 95% (UV 214 nm). | |
With hydrogenchloride; butyl nitrate In methanol; water at 40℃; for 0.5h; | ||
With hydrogenchloride; methanol; butyl nitrate; water at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2.5h; Heating; | |
70% | With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane for 3h; Heating; Irradiation; | |
50% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 1h; Reflux; |
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2h; Heating; Irradiation; | ||
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 3h; | 1.A Example 1; 5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; Step A. 3-Bromo-5-methoxy-1-indanone. (Scheme 1) N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2'-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then-washed with CH2Cl2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C10HgBrO2+H: 241, observed: 241. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium azide; sulfuric acid In benzene at 60℃; for 4h; | |
60% | With sodium azide In methanesulfonic acid; dichloromethane at 20℃; Cooling; | 4.1.2. General procedure for the synthesis of intermediates 9 and 10 General procedure: According to previously reported method [26], 5-methoxy-1-indanone (4.30 g, 26.6 mmol) or 5-fluoro-1-indanone (4.00 g,26.6 mmol) were dissolved in the mixed solvent of CH2Cl2 (40 mL)and MeSO3H (methanesulfonic acid, 40 mL). NaN3 (3.46 g,53.2 mmol) was added slowly in an ice-water bath. Then themixturewas stirred overnight at room temperature. In an ice-waterbath, 20% NaOH (aq) was added to make the solution neutral. Theaqueous solution was extracted with CH2Cl2 and the obtainedorganic layer was combined, washed with brine, dried over MgSO4and concentrated. The residue was purified by silica gel flashchromatography (EtOAc/hexane = 2/1). 4.1.2.1. 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (9).White solid (2.82 g, 60%). 1H NMR (400 MHz, CD3OD) δ 7.93 (d,J = 8.6 Hz, 1H), 6.95 (dd, J = 8.6, 2.4 Hz, 1H), 6.89 (d, J = 1.8 Hz, 1H),3.91 (s, 3H), 3.54 (t, J = 6.7 Hz, 2H), 3.02 (t, J = 6.7 Hz, 2H); ESI-MS:m/z 176.0 [M-H]-. |
60% | With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; | 3 (3) Synthesis of intermediates 3 and 4 The starting material 5-methoxy-1-indanone (4.30, 26.6 mmol) was dissolved in a mixture of 40 mL of dichloromethane and 40 mL of methanesulfonic acid, and cooled to 0 ° C in an ice bath.Sodium azide (3.46 g, 53.2 mmol) was added to the reaction flask and stirred at room temperature overnight. After the completion of the reaction, the reaction solution was slowly added with a 20% sodium hydroxide solution to adjust the pH to a weakly basic state, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium Separation and purification (petroleum ether: ethyl acetate = 1 : 2) gave white solid intermediate 3 (2.82 g, 60%). The synthesis of the intermediate 4 was carried out by the above-prepared compound 5-fluoro-1-oxanone (4.00 g, 26.6 mmol) to give a white solid 4 (2.32 g, 53%). |
49% | With sodium azide; sulfuric acid In benzene at 0 - 60℃; for 24h; | 1.a EXAMPLE 1; 6-(3-Fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one; [0255] a) 6-Methoxy-3,4-dihydro-2H-isoquinolin-1-one Sulfuric acid (82.6 mL) was carefully added, at 0° C., to 5-methoxy-1-indanone (25 g, 154 mmol) in benzene (400 mL) followed by sodium azide (18 g, 277.4 mmol). The resulting mixture was heated at 60° C. for 24 h. After cooling at room temperature, the benzene was evaporated and the resulting mixture was diluted with water and extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation the product was obtained as a white solid after purification by chromatography (SiO2, ethyl acetate/n-hexane 1:1 to 4:1 v:v gradient) (13.2 g, 49%). MS: m/e=177.2 (M+) |
0.300 g (27%) | With methanesulfonic acid | 14.1 3,4-Dihydro-6-methoxy-1(2H)-isoquinolinone Step 1 3,4-Dihydro-6-methoxy-1(2H)-isoquinolinone 5-Methoxyindan-1-one (1.0 g, 6.17 mmol) was placed in round bottom flask. Methanesulfonic acid (10 mL) was added and placed under nitrogen and cooled to 0° C. Sodium azide (0.42 g, 6.8 mmol) was added slowly over 0.5 hour, while the solution was cooled and stirred. The solution was allowed to stir for 2 hours. The solution was quenched with water and extracted with dichloromethane (3*50 mL). The organic layer was washed with sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was triturated with ether and slight amount of ethyl acetate to afford 0.300 g (27%) of the desired product. 1H NMR (DMSO-d6) δ7.76 (m, 1H), 6.87 (m, 2H), 3.79 (s, 3H), 3.33 (m, 2H), 2.85 (m, 2H). Anal. Calcd for C10H11NO2: 178.0868 (M+H). Found: Mol. Wt, 178.0859 (M+H, HRMS). |
In trifluoroacetic acid | 111.1 (1) (1) 6-Methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline To a solution of 5-methoxy-1-indanone (1.0 g) in TFA (20 ml) is added sodium azide (4.0 g), and the mixture is refluxed for 1.5 hour. After cooling, the reaction mixture is poured into water (100 ml), and the pH value of the mixture is adjusted to pH 7 with sodium hydrogen carbonate. The mixture is extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, chloroform/methanol=20:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (470 mg) as a pale brown powder. 1 H-NMR (CDCl3) δ (ppm): 2.97 (2H, t, J=6.5 Hz), 5.35 (2H, ddd, J=2.9, 6.5, 6.5 Hz), 3.85 (3H, s), 6.38 (1H, s), 6.71 (1H, d, J=2.6 Hz), 6.86 (1H, dd, J=2.6, 8.5 Hz), 8.02 (1H, d, J=8.5 Hz) | |
With sodium azide In methanesulfonic acid; dichloromethane at 0 - 20℃; | ||
With hydrogenchloride; sodium azide In water at 0 - 20℃; | General procedure for the synthesis of 3,4-dihydroisoquinolin-1(2H)-one derivatives General procedure: To a solution of the appropriate indan-1-one (1.5 mmol) in 37% HCl (5 mL) at 0 °C NaN3 (0.2 g, 3.0 mmol) was cautiously added. The mixture was stirred overnight at room temperature. The mixture was poured into ice and made basic with Na2CO3. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The collected organic phases were dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by column chromatography with CH2Cl2/AcOEt (9:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With iodosylbenzene; racemic (salen)Mn(III) In acetonitrile at 0℃; for 3h; | |
1: 54% 2: 16% | With aluminum oxide; potassium permanganate; water In 1,2-dichloro-ethane for 85h; Ambient temperature; | |
1: 54% 2: 16% | With aluminum oxide; potassium permanganate for 85h; Ambient temperature; |
1: 30 % Chromat. 2: 8% | With oxygen In acetic acid at 22℃; for 7h; | |
With tert.-butylhydroperoxide; C56H53ClN3P2Ru(1+)*F6P(1-) In benzene at 25℃; for 18h; Inert atmosphere; Schlenk technique; Overall yield = 65 %; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium hydroxide In ethanol for 1h; Ambient temperature; | |
81% | With sodium methylate In methanol at 20℃; | |
76% | With potassium hydroxide In methanol at 20℃; | General procedure for preparation of compounds 6a-d General procedure: Commercially available 1-indanone or 5-methoxy-1-indanone (2 mmol) and the appropriatebenzaldehyde (2 mmol) were suspended in methanol (5 mL) containing KOH (4.7%). The reactionwas stirred at room temperature for 2-4 h. The reaction progress was monitored using silica gel TLCwith petroleum ether:ethyl acetate (2:1) serving as mobile phase. Upon completion, cold water (20mL) was added. The resulting precipitate was collected by filtration and the crude thus obtained waspurified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With trichlorophosphate at 0 - 10℃; for 1h; | General procedure for the synthesis of 1-chloro-2-formyl indenes and tetralenes: General procedure: Indanone Or tetralone (2 mmol) was taken in dry dimethylformamide (1 mL) and stirred at 0-10 ° C in an ice bath. To this phosphorus oxychloride (0.5 mL, 836 mg, 5.43 mmol) was added and further stirred for 1 h. On completion, the reaction mixture was poured in crushed ice, extracted with ethyl acetate, washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The desired 1-chloro-2-formyl indenes/tetralenes were obtained either solid or oil. In some of the cases chromatographic purification was done through silica gel column and hexane-ethyl acetate as eluents. |
With trichlorophosphate 1.) 0 deg C, 2.) 0 deg C; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium-t-butoxide In diethyl ether; <i>tert</i>-butyl alcohol for 7h; Heating; | |
80% | Stage #1: 5-methoxy-1-indanone With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Reflux; Stage #2: iodomethane In tetrahydrofuran; mineral oil for 3h; Inert atmosphere; Reflux; | 4.1.1. 5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (9) NaH (3.7g, 60% w/w suspension in mineral oil) was placed in a round bottom flask and washed with petroleum ether (3×5mL), and dry THF (50mL) was added to it. 5-Methoxy-1-indanone 8 (5.0g, 30.86mmol) in THF was added slowly to the reaction mixture at 0°C and then it was refluxed for 1h under nitrogen atmosphere. The reaction mixture was cooled in ice-bath and methyl iodide (10mL, excess) was added. After which the reaction mixture was further refluxed for 3h. The reaction mixture was placed in an ice bath and quenched by careful addition of cold water. Excess solid NaCl was added to the reaction mixture and stirred vigorously. THF layer was separated and aqueous layer was extracted with ethyl acetate (3×20mL). The combined organic extract was washed with brine (10mL) and dried over Na2SO4. Solvent was removed under vacuum and residue was purified by column chromatography on silica gel. Elution with petroleum ether-ethyl acetate (95:5) gave the product 9 (4.7g, 80%) as a colorless liquid [Rf=0.5 petroleum ether/ethyl acetate (95:5)]. IR (film) νmax: 2953, 1742, 1610cm-1. 1H NMR (400MHz, CDCl3): δ 7.67 (d, J=8.4Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 2.93 (s, 2H), 1.20 (s, 6H). 13C NMR (100MHz, CDCl3): δ 209.8, 165.6, 155.2, 128.6, 126.2, 115.5, 109.9, 55.7, 45.7, 43.1, 25.5. HRMS (ESI) (m/z): found 213.0885 (M+Na)+; calcd for C12H14NaO2: 213.0886. |
80% | Stage #1: 5-methoxy-1-indanone With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; |
68% | With potassium-t-butoxide In diethyl ether; <i>tert</i>-butyl alcohol for 6h; Cooling with ice; Reflux; | 26.I Step I: Step I: Preparation of 5-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (26-1) The compound 5-methoxy-2,3-dihydro-1-indenone (1.5 g, 9.3 mmol) was dissolved in ether (40 mL), and followed by dripping with iodomethane (2.9 mL, 46.2 mmol) in ice bath. Then in the ice bath, the mixture was added with the solution of potassium tert-butanol (3.4 g, 30.4 mmol) in tert-butanol (20 mL) and reacted at reflux for 6 hours. Water was added to quench the reaction, and the reaction solution was extracted twice with ether. The organic phase was washed with a saturated saline solution. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated by column chromatography to afford the target molecules (1.2 g, 68 %). |
41% | Stage #1: 5-methoxy-1-indanone With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - 20℃; for 1h; Stage #2: iodomethane In tetrahydrofuran; hexane for 2.5h; | |
With sodium hydride In 1,2-dimethoxyethane | ||
With potassium hydroxide; 18-crown-6 ether Heating; | ||
With sodium hydride In tetrahydrofuran | ||
Stage #1: 5-methoxy-1-indanone With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.166667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at 0 - 40℃; for 3.5h; Inert atmosphere; | ||
Stage #1: 5-methoxy-1-indanone With potassium-t-butoxide In tetrahydrofuran at 0 - 10℃; for 1h; Stage #2: iodomethane In tetrahydrofuran at 0 - 10℃; for 1h; | 4.1 (1) The first step: 5-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (5-methoxy-2,2-dimethyl-2,3-dihydro) Preparation of Hydrogen-1-Indanone) Tetrahydrofuran (10ml, 10V) was added to the reaction flask, nitrogen was replaced three times, and the internal temperature was lowered to 0°C. Control the internal temperature 0-10,Potassium tert-butoxide (1.52 g, 2.2 eq) was added, and the mixture was heated and stirred for 10 min after the dropwise addition. Control the internal temperature to 0-10°C, add dropwise a solution of 5-methoxy-1-indanone in tetrahydrofuran (1g, THF10ml),After the dropwise addition was completed, the temperature was kept at 0-10 °C and stirred for 1 h, and methyl iodide (2.27 g, 2.6 eq) was added dropwise, and the exotherm was obvious.Control the temperature to 0-10°C, and stir for one hour after the dropwise addition. The HPLC control indicated that the reaction was complete.Stop the reaction, carry out post-treatment, add water (2.5ml, 2.5V) and stir for 10min under temperature control at 5-20°C, add 1M dilute hydrochloric acid (2.5ml, 2.5V) and stir for 30min. EA (total 6 ml, 6V) was extracted twice, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure at 40°C to obtain 5-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one as a colorless liquid. Yield quantification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.24% | With sodium acetate In ethanol for 24h; Ambient temperature; | |
52% | With sodium acetate; sodium sulfate In ethanol at 95℃; for 7h; Irradiation; | General method for the synthesis of IN1-6 General procedure: General method for the synthesis of IN1-6 A mixture of corresponding 1-indanone (1 equiv), Na2SO4 (4 equiv), anhydrous NaOAc (2 equiv), and N-methylhydroxylamine hydrochloride (2 equiv), in dry EtOH, was irradiated in a microwave apparatus (Biotage) at 95 °C, 250 W, and 20 atm, for the time indicated in each case. Then, the mixture was cooled, the solvent was removed, toluene was added to eliminate traces of AcOH, and the residue purified by column chromatography to give the desired indanonitrone, that was recrystallized from AcOEt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Example F[0155] 6-Methoxy-chroman-2-one[0156] 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml of dichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) was added portionwise, and the reaction mixture was stirred at 0ВC for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification. |
80% | With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | a) 6-Methoxy-chroman-2-one To a solution of 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml of dichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) was added portionwise, and the reaction mixture was stirred at 0 C. for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification. |
80% | With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml of dichloromethane cooled in an ice bath was added sodium bicarbonate (4.35 g, 51.8 mmol). 3-Chloro-peroxybenzoic acid (11.61 g, 51.8 mmol) was added portionwise and the reaction mixture was stirred at 0Stirred for 2 h and stirred at room temperature overnight.The precipitate was filtered and washed with dichloromethane. The filtrate was washed with a saturated solution of sodium bicarbonate and dried over sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) as an orange oil was obtained which was used without further purification. |
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Example F2-Pyrazin-2-yl-chroman-6-ola) 6-Methoxy-chroman-2-oneTo a solution of 5-methoxy-indan-1 -one (4.2 g, 25.9 mmol) in 240 ml ofdichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51 .8 mmol). 3-Chloro-perbenzoic acid (1 1 .61 g, 51 .8 mmol) was added portionwise, and the reaction mixture was stirred at 0C for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification. | |
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Example F2-Pyrazin-2-yl-chroman-6-ola) 6-Methoxy-chroman-2-oneTo a solution of 5-methoxy-indan-1 -one (4.2 g, 25.9 mmol) in 240 ml ofdichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51 .8 mmol). 3-Chloro-perbenzoic acid (1 1 .61 g, 51 .8 mmol) was added portionwise, and the reaction mixture was stirred at 0C for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification. | |
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 18h;Inert atmosphere; | 5-methoxy-indan-1-one (1.62 g, 10.0 mmol, 1.0 equiv) in 100 mL of DCM cooled to 0 C was added NaHCO3 (1.7 g, 20 mmol, 2.0 equiv). To this, 3-chloro-perbenzoic acid (4.5 g, 20 mmol, 2.0 equiv) was added portion wise, and the reaction mixture was stirred at 0 C for 2 h and at room temperature for 16 h. The precipitate was filtered off and washed with DCM. The filtrate was washed with saturated solution of NaHCO3 and dried over Na2SO4. After evaporation of the solvent under vacuum 6-methoxy-chroman-2-one was obtained as brown oil (1.5 g, 84%), which was used without further purification. | |
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | To a solution of 5-methoxy-indan-1 -one (4.2 g, 25.9 mmol) in 240 ml ofdichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51 .8 mmol). 3-Chloro-perbenzoic acid (1 1 .61 g, 51 .8 mmol) was added portionwise, and the reaction mixture was stirred at 0C for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 5-methoxy-1-indanone In tetrahydrofuran at 20℃; Stage #2: Methyl 2-bromopropionate With zinc In tetrahydrofuran at 50℃; for 20h; | A.1 In an oven dried 3-neck 5.0 L flask fitted with a condenser, a thermometer, and an addition funnel was charged under argon, 5-methoxy-1-indanone (86.73 g, 0.52 mol) and THF (2.13 L). The mixture was stirred at rt and became an orange-colored solution. Zinc granules (59.96 g, 0.92 mol, 30 mesh) were added to this solution. The mixture was heated to-50C with simultaneous addition of a solution of methyl-2-bromopropionate (88.80 g, 0.79 mol) in THF (393 mL). The reaction mixture was heated for a period of 20 h, after which heating was stopped and the reaction mixture cooled to rt followed by cooling on an ice bath. The mixture was then slowly quenched with HCI (3.3 L, 1 N aqueous solution) maintaining the internal temperature [AT ~18C.] The aqueous layer was extracted with EtOAc (3 x 500 mL). The organic layer was then washed with water (4 x 500 mL, a pH [OF-4.] 5 achieved), brine (500 mL), and dried over [NA2SO4.] The solvent was removed under vacuum to give a dark brown colored oil. The crude product was purified by silica gel chromatography (1-8% EtOAc/hexane gradient) to give 54.09 g (52%) of the title compound as a dark brown [OIL.'H] NMR (400 MHz, DMSO-d6): [# ] 7.25 (1H, d), 7.09 (1H, s), 6.87 (1H, dd), 6.24 (1H, s), 3.82 [(1H,] q), 3.75 (3H, s), 3.58 (3H, s), 3.30 (2H, s), 1.21 (3H, d); LC-MS: RT = 3.00 min, M+H+ : 233.0. |
With zinc In tetrahydrofuran at 60℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | An oven dried 5.0 L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under an argon atmosphere, a suspension [OF 5-METHOXY-1-INDANONE] (80.0 g, 494 [MMOL)] and Zn powder (Lancaster, 56.2 g, 865 [MMOL)] in THF (2 L, anhydrous) was stirred at [60C] (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 [MMOL)] in THF (400 mL, anhydrous) was added slowly using an addition funnel. After completion of the addition, the reaction mixture was stirred at [60C] (internal temperature) for 1 h. The reaction was analyzed by TLC, and once complete, followed by a [1 N] aqueous HCI workup. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of [HCI] (3 L, 1 N aqueous solution). The internal temperature was kept below [20C.] The mixture was then extracted with EtOAc (1 L). The organic layer was washed with water until pH 6.0-7. 0, then with brine, dried over [NA2SO4,] and filtered. The product (127g, >99%), a yellow oil, was obtained after solvent removal and drying under [VACUUM. 1H NMR] (300 MHz), [(DMSO-D6) 6] 7.28 (d, [1H),] 7.05 (d, [1H),] 6.82 (dd, [1H),] 6.22 (s, 1H), 3.72 (s, 3H), 3.60 (m, [1H),] 3.58 (s, 3H), 3.28 (s, 2H), 1.95 (m, [1H),] 1.80 (m, 1H), 0.88 (t, 3H). | |
> 99% | Example 1Preparation of methyl 2-(6-methoxy-lH-inden-3-yl) butanoateAn oven dried 5 -L four-necked round -bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-l-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous TEtaF was stirred at 6O0C (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 74] mmoi) in 400 inL anhydrous TEtaF was added slowly through an addition funnel After completion of the addition, the reaction mixture was stirred at 6O0C (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following IN aqueous HCl work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of IN HCl solution. The pot temperature was kept below 2O0C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0-7.0, then saturated NaCl solution, and dried over Na2SO4, The product (127 g, >;99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (DMSO-t,) delta 7.28(d, IH), 7.05(d, IH), 6.82(dd, IH), 6.22(s, IH), 3.72(s, 3H), 3.60(m, IH), 3.58(s, 3H), 3.28(s, 2H), 1.95(m, IH), 1.80(m, IH), 0.88(t, 3H). | |
> 99% | With zinc; In tetrahydrofuran; at 60℃; for 1h;Inert atmosphere; | An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous THF was stirred at 60 C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in 400 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at 60 C. (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following 1N aqueous HCl work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of 1N HCl solution. The pot temperature was kept below 20 C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0-7.0, then saturated NaCl solution, and dried over Na2SO4. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (DMSO-d6) delta 7.28 (d, 1H), 7.05 (d, 1H), 6.82 (dd, 1H), 6.22 (s, 1H), 3.72 (s, 3H), 3.60 (m, 1H), 3.58 (s, 3H), 3.28 (s, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 0.88 (t, 3H). |
> 99% | With zinc; In tetrahydrofuran; at 60℃; for 1h;Inert atmosphere; | An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous THF was stirred at 60 C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in 400 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at 60 C. (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following 1N aqueous HCl work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of 1N HCl solution. The pot temperature was kept below 20 C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0-7.0, then saturated NaCl solution, and dried over Na2SO4. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (DMSO-d6) delta 7.28 (d, 1H), 7.05 (d, 1H), 6.82 (dd, 1H), 6.22 (s, 1H), 3.72 (s, 3H), 3.60 (m, 1H), 3.58 (s, 3H), 3.28 (s, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 0.88 (t, 3H). |
With hydrogenchloride; In tetrahydrofuran; | Example 1 Preparation of Methyl 2-(6-methoxy-1H-inden-3-yl) Butanoate An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous THF was stirred at 60 C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in 400 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at 60 C. (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following 1 N aqueous HCl work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of 1 N HCl solution. The pot temperature was kept below 20 C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0-7.0, then saturated NaCl solution, and dried over Na2SO4. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (DMSO-d6) delta 7.28(d, 1H), 7.05(d, 1H), 6.82(dd, 1H), 6.22(s, 1H), 3.72(s, 3H), 3.60(m, 1H), 3.58(s, 3H), 3.28(s, 2H), 1.95(m, 1H), 1.80(m, 1H), 0.88(t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10%; 90% | With trifluorormethanesulfonic acid; In dichloromethane; at 80℃; for 1h;High pressure; Inert atmosphere; Green chemistry; | General procedure: Trifluoromethane sulfonic acid (3 eq.) was gently added to a cooled (0 C) solution of a 3-Phenylpropionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in a 12 mL Q-tube pressure tube, furnished by QLabtech. The temperature was raised to room temperature. A Teflon septum was placed on the top of the tube and the appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 80 C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried on Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the crude by flash chromatography. |
With polyphosphoric acid; at 80℃; for 4h;Inert atmosphere; | 4.5 5-Methoxy-2,3-dihydro-1H-inden-1-one 5 3-(3-Methoxy phenyl)propanoic acid (1.0 g) was reacted with polyphosphoric acid (4.0 g) at 80 C for 4 h and then poured onto ice cold water stirred for 30 min. and extracted into ethyl acetate (3 * 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5-methoxy-2,3-dihydro-1H-inden-1-one and 7-methoxy-2,3-dihydro-1H-inden-1-one in a 4:1 in 80:20% yield. 1H NMR (CDCl3, 300 MHz): delta 7.52 (t, 1H, Ar-H, J = 8.0, 7.6 Hz), 7.02 (d, 1H, Ar-H, J = 7.9 Hz), 6.79 (d, 1H, Ar-H, J = 7.8 Hz), 3.95 (s, 3H, OCH3), 3.09 (t, 2H, CH2, J = 6.2, 5.9 Hz), 2.68 (t, 2H, CH2, J = 6.1, 5.9 Hz). MS (ESI): m/z 163 (M+H)+; HRMS: Calcd for C10H11O2: 163.07498. Found: 163.07536. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-Bromosuccinimide; sulfuric acid In water at 60℃; for 5h; | |
With N-Bromosuccinimide In water at 20℃; Irradiation; | ||
With N-Bromosuccinimide In water at 20℃; Darkness; | 10.1 4-Bromo-5-methoxy-indane-1-one Step 1: 4-Bromo-5-methoxy-indane-1-one 5-Methoxy-indane-1-one (17.2 g, 106.05 mmol) is suspended in 100 mL of water. The flask is covered with an aluminium foil to create a dark environment. N-Bromo-succinimide (18.87 g, 106.05 mmol) is added portionwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is extracted with 200 mL of ethyl acetate, the organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product obtained (20 g) is used in the next step without any further treatment. LC (LC METHOD 7): tR=2.70 min; Mass spectrum (ES+): m/z=241 [M+H]+. |
With N-Bromosuccinimide In water at 20℃; Darkness; | Step 1: 4-Bromo-5-methoxy-indane-1-one Step 1: 4-Bromo-5-methoxy-indane-1--Methoxy-indane-1-one (17.2 g, 106.05 mmol) is suspended in 100 ml of water. Theflask is covered with an aluminium foil to create a dark environment. N-Bromo-succinimide(18.87 g, 106.05 mmol) is added portionwise and the reaction mixture is stirred at roomtemperature overnight. The reaction mixture is extracted with 200 ml of ethyl acetate, theorganic phase is collected, dried over sodium sulfate and concentrated under vacuum. Thecrude product obtained (20 g) is used in the next step without any further treatment.LC (LC METHOD 7): tR = 2.70 min; Mass spectrum (ES+): m/z = 241 [M+Hr. | |
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In water at 20℃; | A Step A: 5-Methoxy-2,3-dihydro-lH-inden-l-one (30.0 g, 0.19 mol, 1.0 eq) and l,3-dibromo-5,5- dimethylhydantoin (52.96 g, 0.19 mol, 1.0 eq) were suspended in H20 (300 mL) and the mixture was stirred overnight at room temperature. Then the mixture was filtered and the filter cake was washed with water (3x100 mL). The filtrate was extracted with EtOAc (500 mL). The organic layer was separated, washed with water (200 mL), brine (200 mL), dried over Na2S04, and concentrated. The resulting residue was triturated in IPAc (100 mL) to give 4-bromo-5- methoxy-2,3-dihydro-lH-inden-l-one. 1HNMR (400MHz , CDC13): δ 7.72 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.01 (s, 3H), 3.09-3.05 (m, 2H), 2.74-2.71 (m, 2H). | |
With N-Bromosuccinimide; sulfuric acid In water at 60℃; for 6h; | 3.1 Step1: 4-Bromo-5-methoxy-2,3-dihydro-1H-inden-1-one N-Bromosuccinimide (1.0 eq.) was added to a solution of 5-methoxy-2,3-dihydro-1H-inden-1-one (1.0 eq.) in water (0.1 M) and the reaction mixture was heated to 60. 40% aqueous sulfuric acid solution (2.0 eq.) was added and stirred at 60 for 6 h. The crude product was extracted with tert-butyl methyl ether and dried over magnesium sulfate, filtered and concentrated. Then, the mixture was additionally purified bycrystallization using ethanol to give pure 4-bromo-5-methoxy-2,3-dihydro-1H-inden-1-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydride In tetrahydrofuran at 70℃; for 12h; Inert atmosphere; | |
76% | With sodium hydride In various solvent(s) at 90℃; for 0.5h; | |
69% | With sodium hydride; sodium tertiary butoxide at 0 - 20℃; Inert atmosphere; |
66% | With sodium hydride; sodium tertiary butoxide In tetrahydrofuran; mineral oil at 20℃; for 16h; | |
46% | With sodium hydride In toluene; mineral oil at 0 - 120℃; for 18h; | |
Stage #1: 5-methoxy-1-indanone; carbonic acid dimethyl ester With sodium hydride; <i>tert</i>-butyl alcohol In tetrahydrofuran Reflux; Stage #2: With acetic acid In tetrahydrofuran at 0℃; | ||
With sodium hydride In mineral oil at 80℃; for 3h; Inert atmosphere; | ||
With sodium hydride In toluene; mineral oil Schlenk technique; Inert atmosphere; Reflux; | ||
With sodium hydride In mineral oil at 80℃; Inert atmosphere; Schlenk technique; | ||
With potassium-t-butoxide; sodium hydride at 20℃; for 1h; Inert atmosphere; | General procedure for the synthesis of 2a-g. General procedure: In an ice bath, anhydrous dimethyl carbonate (30 mL) was added to a mixture of 95% NaH (3.03 g, 120 mmol) and potassiumtert-butoxide (4.2 g, 37.5 mmol). And then, a solution of indenone (30 mmol) in anhydrous dimethyl carbonate (70 mL) was added dropwise under argon. The mixture was stirred at room temperature for 1 h and adjusted pH to 2-3 with diluted HCl. The organic layers were collected and washed with brine (2 × 100 mL), dried over MgSO4, filtered and concentrated in vacuum to obtain the corresponding crude compounds 2a-g. The crude products were used in the next reaction without further purification. | |
With potassium-t-butoxide; sodium hydride at 0℃; Inert atmosphere; | ||
at 80℃; for 1h; | ||
With sodium hydride In mineral oil for 12h; Reflux; | ||
Stage #1: carbonic acid dimethyl ester With potassium-t-butoxide; sodium hydride In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: 5-methoxy-1-indanone In tetrahydrofuran at 20℃; for 2h; | ||
With sodium hydride In tetrahydrofuran; mineral oil Reflux; | 1. β-keto amides General procedure: β-keto methyl esters were prepared according to the literature procedures (Eur. J. Org. Chem.-6530;).2010, 34, 6525NaH (50 mmol, 2.5 g, 2.5 equiv., 60% dispersion in mineral oil) andanhydrous dimethyl carbonate (DMC, 5 mL)andanhydrous THF (100 mL) were addedsequentially to a dry three-necked flask equipped with a septum, condenser, argon inlet, and alarge stirring egg. The 1-indanone (20 mmol, 1 eq), solubilized in anhydrous THF (20 mL),was added via a dropping funnel for the course of 30 minutes. The heterogeneous mixturewas brought to reflux, and heated for 6 h at this temperature. The reaction was allowed to cooland cautiously quenched at 0 C with H2O (10 mL). The mixture was transferred to aseparative funnel with EtOAc while adding additional 50 mL of 1M HCl. The reaction wasextracted with EtOAc (50 mL x 3) and the combined organic layers washed with a saturatedbrine solution before being dried over solid anhydrous magnesium sulfate and the crudemethyl esters was purified by column chromatography. -keto amides 1a-1v were prepared745).according to the literature procedure (Adv. Synth. Catal. 2016, 358, 737-To a flask equipped with a reflux condenser was added -keto methyl ester (1 mmol), correspondingmmol).amidesR4NH(1.5The mixture was refluxed until complete conversion wasobserved by TLC, then concentrated under reduced pressure and the crude residue waspurified by column chromatography and recrystallization. The 1-indanone derivates werepurchased from Energy-Chemical, Aladdin and Adamas |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; sodium methylate In methanol at 20℃; | ||
With hydrogen; sodium methylate In methanol at 20℃; for 65h; | 2.1 Step 1: 2-(2-hydroxyethyl)-5-methoxy-1-indanone A solution of 5-methoxy-1-indanone (500 mg, 3.08 mmol) in methanol (10 mL) was treated with 10% palladium on carbon (53 mg) followed by glycoaldehyde dimer (370 mg, 3.08 mmol) and 0.5M sodium methoxide in methanol (1.3 mL, 0.65 mmol). The mixture was placed under a hydrogen atmosphere (balloon) and stirred vigorously at room temperature for 65 hours. After purging with nitrogen, the mixture was filtered through a 0.45 μm Acrodisc and the disk was rinsed with methanol (2 mL). The filtrate was diluted with EtOAc (25 mL), washed with 0.1N HCl (15 mL) and brine (15 mL), dried over MgSO4, filtered, and evaporated under vacuum to a solid. LC-MS of this material showed a mixture of starting material (major) and product. The mixture was purified by chromatography on a Biotage Flash 12M KP-Sil column (12 mm*15 cm). The column was eluted with 3:2 EtOAc-hexanes, collecting 6 mL fractions every 30 sec. Fractions 20-36 were concentrated under vacuum and flashed with benzene to afford 2-(2-hydroxyethyl)-5-methoxy-1-indanone as an oil. 1H NMR (CDCl3, 500 MHz) δ 1.80 and 2.05 (two m, CH2CH2OH), 2.79 and 3.35 (two dd, 3-CH2), 2.83 (m, H-2), 3.77-3.90 (m, CH2CH2OH), 3.87 (s, OCH3), 6.86 (d, H-4), 6.89 (dd, H-6), and 7.67 (d, H-7). | |
With hydrogen; sodium methylate In methanol at 20℃; for 65h; | 2.1 A solution of 5-methoxy-l-indanone (500 mg, 3.08 mmol) in methanol (10 mL) was treated with 10% palladium on carbon (53 mg) followed by glycoaldehyde dimer (370 mg, 3.08 mmol) and 0.5M sodium methoxide in methanol (1.3 mL, 0.65 mmol). The mixture was placed under a hydrogen atmosphere (balloon) and stirred vigorously at room temperature for 65 hours. After purging with nitrogen, the mixture was filtered through a 0.45 μm Acrodisc and the disk was rinsed with methanol (2 mL). The filtrate was diluted with EtOAc (25 mL), washed with 0. IN HCl (15 mL) and brine (15 mL), dried over MgSOφ filtered, and evaporated under vacuum to a solid. LC-MS of this material showed a mixture of starting material (major) and product. The mixture was purified by chromatography on a Biotage Flash 12M KP-SiI column (12 mm x 15 cm). The column was eluted with 3:2 EtOAc-hexanes, collecting 6 mL fractions every 30 sec. EPO Fractions 20-36 were concentrated under vacuum and flashed with benzene to afford 2-(2-hydroxyethyl)- 5-methoxy-l-indanone as an oil. 1H NMR (CDCl3, 500 MHz) δ 1.80 and 2.05 (two m, CH2CH2OH), 2.79 and 3.35 (two dd, 3-CH2), 2.83 (m, H-2), 3.77-3.90 (m, CH2CH2OH), 3.87 (s, OCHj), 6.86 (d, H-4), 6.89 (dd, H-6), and 7.67 (d, H- 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With iodine; zinc In tetrahydrofuran at 20℃; for 1.25h; Inert atmosphere; Reflux; | 1.1 EXAMPLE 1Step 1A mixture of 5-methoxy-2,3-dihydro-1H-inden-1-one 1-1 (30.0 g, 185 mmol), zinc dust (21.6 g, 330 mmol), and copper(I) chloride (900 mg, 9.10 mmol) in THF (800 mL) was heated under reflux under N2. Ethyl bromoacetate (15.5 g, 93.3 mmol) and a crystal of iodine were added slowly under reflux. The mixture was refluxed for 15 min, and the heater removed. Then, more ethyl bromoacetate (30.9 g, 187 mmol) was added dropwise maintaining a gentle reflux. The mixture was cooled to room temperature and stirred for 1 h. The precipitate was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo. The same process on the same scale was repeated two times. The three batches were combined by dissolving in EtOAc (1 L) and 1N hydrochloric acid (1 L). The layers were separated. The organic layer was washed with brine, dried over Na2SO2, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with hexanes/EtOAc 19:1) to provide 1-2 (110.0 g, 85%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.15 (t, J=2.4 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.35-3.22 (m, 2H), 3.10-3.00 (m, 2H), 1.31 (t, J=7.1 Hz, 3H). |
With zinc In tetrahydrofuran at 40℃; | ||
Stage #1: 5-methoxy-1-indanone With copper(l) iodide; zinc In tetrahydrofuran for 0.25h; Inert atmosphere; Reflux; Stage #2: ethyl bromoacetate In tetrahydrofuran at 20 - 35℃; Inert atmosphere; | 129 Preparation of ethyl (5-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethanoate To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under Ar atmosphere and refluxed for 15 minutes; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring overnight at rt, TLC showed the presence of desired product, indicating the formation of reactive zinc species. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 hours, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol total) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated in vacuo to a volume of 2 L. The liquid was then poured into sufficient 1N aqueous hydrochloric acid (cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2×1 L, 1×500 mL). The combined extracts were washed with water, brine (1 L each), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark red oil which solidified gradually (438.3 g; theoretical yield=432 g). 1H NMR (CDCl3): δ □ 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (Cl) m/z 233 [M+H]+. |
Stage #1: 5-methoxy-1-indanone With copper(l) chloride; zinc In tetrahydrofuran for 0.25h; Inert atmosphere; Reflux; Stage #2: ethyl bromoacetate In tetrahydrofuran at 20 - 35℃; | 129 Preparation of ethyl (5-methoxy-2,3-dihydro- 1H- inden-1 -ylidene)ethanoate To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under Ar atmosphere and refluxed for 15 minutes; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring overnight at rt, TLC showed the presence of desired product, indicating the formation of reactive zinc species. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 hours, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned oil leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol total) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned oil. The combined reaction solutions were concentrated in vacuo to a volume of 2 L. The liquid was then poured into sufficient iN aqueous hydrochloric acid (cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2x1 L, 1x500 mL). The combined extracts were washed with water, brine (1 L each), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark red oil which solidified gradually (438.3 g; theoretical yield432 g). ‘H NMR (CDC13): ö 07.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (Cl) mlz 233 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc In tetrahydrofuran at 20 - 35℃; for 16h; | ||
Stage #1: 5-methoxy-1-indanone With zinc In tetrahydrofuran for 0.25h; Heating / reflux; Stage #2: ethyl bromoacetate In tetrahydrofuran at 35℃; for 4h; | D.1 To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper [(L)] chloride (4.53 g, 0.045 mol). The suspension was stirred under argon atmosphere and refluxed for 15 minutes; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring overnight at rt, TLC showed the presence of desired product, indicating the formation of reactive zinc species. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to [35C).] After 4 h, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol). Ethyl bromoacetate (140 mL, 2.36 mol) was added dropwise. An exotherm was observed (internal temperature increased to [35C).] When the stirred mixture cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated in vacuo to a volume [OF-2] L. The liquid was then poured into sufficient 1 N aqueous hydrochloric acid (cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2 x 1 L, 1 x 500 mL). The combined extracts were washed with water, brine [(1] L each), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark red oil which solidified gradually (438.3 g; theoretical yield = 432 g)'H NMR [(CDCI3)] : [6] 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS [(CI)] [M/Z 233 [M+H] +.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol). The resulting mixture was stirred at reflux temperature for 2.5 h, then cooled and filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 C and treated with triethylamine (0.28 mL, 2.0 mmol) overnight, then concentrated in vacuuo. Chromatography of the residue (1 : 9~1 : 4 EtOAc/hexanes) afforded 97 mg (60%) of enone 1a as the pink oil which solidified as light red solid in refrigerator. | |
70% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2.5h;Reflux; | General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol).The resulting mixture was stirred at reflux temperature for 2.5 h, then cooledand filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 C and treated with triethylamine (0.28 mL, 2.0 mmol)overnight, then concentrated in vacuuo. Chromatography of the residue (19~14 EtOAc/hexanes) afforded 97 mg (60%) of enone 1a as the pink oil which solidified as light red solid in refrigerator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 5-methoxy-1-indanone; n-Butyl nitrite In methanol at 45℃; for 0.75h; Stage #2: With hydrogenchloride In water at 45℃; for 1.83333 - 2.33333h; | 2.2.A 2- {2- [1-ETHYL-3- (4-TRIFLUOROMETHOXYPHENYL) UREIDO] INDAN-5-YLSULFANYL}-2- methylpropionic acid.; Compound 2.0 (Example 2); A. 5-METHOXVINDAN-1 2-dione-2-oxime. Scheme 2. To a solution of 5-METHOXYINDAN-1-ONE (75.8 g; 0.467 mol) in MEOH (1.4 L) at 45 °C is added butyl nitrite (81 mL; 0.693 mol) dropwise over 45 min. Concentrated HCI (45 mL) is then added to the hot solution over 20 min and the reaction was allowed to stir at 45 °C for an additional 1.5-2 h. The reaction suspension is cooled, the precipitate filtered, washed several times with cold MEOH, and dried under vacuo to afford 55.8 g (62%) of 5-methoxyindan- 1,2-dione-2-oxime as a beige solid. 1H NMR (300 MHz, CD30D) : 8 7.80-7. 83 (m, 1H), 6.95 (bs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (bs, 1 H) LC/MS: C10HGNO3 : M/Z 192 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 5-methoxy-1-indanone; n-Butyl nitrite In methanol at 45℃; for 0.75h; Stage #2: With hydrogenchloride In water at 45℃; for 1.83333 - 2.33333h; | 2.2.A 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid. Compound 2.0; (Example 2); A. 5-Methoxyindan-1,2-dion-2-oxime Scheme 2. To a solution of 5-METHOXYINDAN-1-ONE (75.8 g; 0.467 mol) in MEOH (1.4 L) at 45 °C is added butyl nitrite (81 mL; 0.693 mol) dropwise over 45 min. Concentrated HCI (45 mL) is then added to the hot solution over 20 min and the reaction was allowed to stir at 45 °C for an additional 1.5-2 h. The reaction suspension is cooled, the precipitate filtered, washed several times with cold MEOH, and dried under vacuo to afford 55.8 g (62%) of 5-methoxyindan- 1,2-dione-2-oxime as a beige solid. 1H NMR (300 MHz, CD30D) : S 7.80-7. 83 (m, 1H), 6.95 (bs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (bs, 1 H) LC/MS: DOHENOS : M/Z 192 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine In dichloromethane at 20℃; for 48h; | 27.1 A suspension of [5-HYDROXY-1-INDANONE] (936 mg, 6 mmol, commercially available), [2- (5-METHYL-2-PHENYLOXAZOL-4-YL) ETHANOL] (1220 mg, 6 [MMOL,] commercially available), ADDP (3028 mg, 12 [MMOL),] and Ph3P (3148 mg, 12 [MMOL)] in 15 mL anhydrous [CH2CI2] was stirred at rt under argon for 48 h. Purification by column chromatography (25% EtOAc/hexane) gave 1320 mg (83%) of the product, a white solid. LC/MS retention time 3.11 min; MS (ES) [[M+1]] 334. [2 H] NMR [(CDCI3)] : [6] 2.40 (s, 3H), 2.65-2. 72 (m, 2H), 3.05-3. 18 (m, 4H), 4.35 (t, 2H, ), 6.95 (d, 2H), 7.53-7. 58 (m, 3H), 7.70 (d, [1H),] 7.89-8. 05 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: 5-methoxy-1-indanone; 1-phenyl-3-thiophen-2-yl-1H-pyrazole-4-carbaldehyde In isopropyl alcohol at 20 - 50℃; Stage #2: With sodium hydroxide In water; isopropyl alcohol at 20 - 50℃; for 3.5h; | 2 To a solution of intermediate 2 (500 mg, 1.97 mmol) : in 4 ml of 2-propanol was added 5-methoxy-indanone (320 mg, 1. 97 mmol) while stirring at room temperature. The reaction mixture was heated to 50°C, and 0.44 ml of 20% aqueous sodium hydroxide was added. The mixture was stirred at 50°C for 0.5 hour, cooled to room temperature and stirred for an additional 3 hours. The precipitate was filtered off and crystallized from 2-propanol to produce 5-METHOXY-2- (1-PHENYL-3-THIOPHEN-2- YL-1H-PYRAZOL-4-YLRNETHYLENE)-INDAN-1-ONE (300 mg, 38%) as a yellow solid. Analytical data C24H18N2O2S MM: 398.49 g. mol' MS (ESI+): 399 RMN'H (400MHZ, CDC13) 5 (PPM) : 3.75 (s, 2H, CH2), 3.83 (s, 3H, MeO), 6.93-6. 95 (dd, 1H, J1 = 1.76, J2 = 8.5, Harom), 6.99 (s, 1H, H) 7.17-7. 19 (t, 1 H, J = 4. 4, H), 7.36-7. 4 (t, 1H, J = 7. 32, H), 7. 43 (d, 1H, J = 5, Harom), 7.48 (d, 1H, J = 3. 5, Harom), 7. 5-7.55 (t, 2H, J = 7. 6, H), 7.81-7. 83 (M, 4H,, Harom)/8. 2 (s, 1H, HPYR2ZOLE). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With titanium tetrachloride In dichloromethane; toluene at -45 - 25℃; for 3h; | 26(a) To a stirred solution of titanium chloride (4.91 g, 25.9 mmol) in anhydrous dichloromethane (30 ml) was added 1.01 M dimethyl zinc toluene solution (25.6 ml, 25.9 mmol) at -45° C. under nitrogen and the mixture was stirred for 10 minutes at -45° C. To the mixture was added a solution of 5-methoxy-1-indanone (2.0 g, 12.3 mmol) in anhydrous dichloromethane (15 ml) dropwise at -45° C. and the mixture was warmed to ambient temperature. After 3 hours at ambient temperature, the mixture was poured into ice-water and the aqueous solution was extracted with ethyl acetate (x 3). The combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with hexane/ethyl acetate =50/1-30/1 to furnish 941 mg (43% yield) of the title compound as colorless oil. 1H NMR (270 MHz, CDCl3) δ ppm 1.23 (6H, s), 1.88-1.96 (2H, m), 2.82-2.90 (2H, m), 3.78 (3H, s), 6.70-6.78 (2H, m), 7.00-7.07(1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate In acetone at 20℃; for 18h; Inert atmosphere; | |
33% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h; | A; 2102.A A mixture of 5-hydroxy-indan-1-one (125 mg), K2CO3 (350 mg), methyl iodide (263 μL) in DMF (4 mL) was stirred at 50° C. for 3 h and poured into 1N hydrochloric acidl (20 mL) and washed with Et2O (4×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the intermediate as a clear oil (44.7 mg; 33%). [MH]+=163. |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere; | 70 To a solution of 5-hydroxy-2,3-dihydroinden-1-one (1.48 g, 10.0 mmol) in dry DMF (20 mL) were added iodomethane (7.1 g, 50.0 mmol) and K2C03 (2.76 g, 20 mmol). The mixture was stirred at room temperature for 20 h under N2 atmosphere. The resulting mixture was quenched by water (100 mL), extracted with EtOAc (2 x 100 mL) and washed with brine (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give the crude compound SP-0010529-138 as a brown solid (1.9 g of the crude). LC-MS 163 (M+H), purity 95% (UV 214 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With formaldehyd;potassium hydroxide; In ethanol; | c 2,3-Dihydro-5-methoxy-2-methyl-1H-inden-1-one 5-Methoxy indanone was treated with aqueous formaldehyde in the presence of iron pentacarbonyl and KOH in ethanol according to G. Cainelli et. al., Tetrahedron Letters 27, 2491 (1973). After chromatography (hexane:ethylacetate=7:3) over SiO2, a 44% yield of white crystals was obtained (m.p. 73-76 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | acetic acid; In ethanol; for 1h;Heating / reflux; | 5-Methoxy-1-indanone(4-Benzyloxyphenyl)-hydrazone A solution of <strong>[51145-58-5]4-benzyloxyphenylhydrazine</strong> [51145-58-5]* (10.0 g, 51 mmole) and 5-methoxy indanone [5111-70-6]** (9g, 55 mmole) and a few drops of AcOH in EtOH (100 ml) was heated to reflux for 1 hr. The reaction was then cooled and a solid precipitated out. The solid was filtered to give 14 g of a tan solid (80%). 1H NMR (DMSO) 11.88 (s, 1 H), 7.48 (d, 1 H, J = 8.4 Hz), 7.43-7.32 (m, 5 H), 7.08 (d, 2 H, J = 9.0 Hz), 6.88 (m, 3 H), 6.81 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.17 (s, 2 H), 3.75 (s, 3 H), 3.03 (t, 2 H, J = 6.6 Hz), 2.73 (t, 2 H, J = 6.5 Hz); IR (KBr) 3350, 1520, 1250 cm-1; CHN calc for C23H22N2O2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; n-Butyl nitrite In methanol; water at 40℃; for 2h; | 2.a To a solution of 5-methoxy-l-indanone (25g, 0.15mol) in 300ml MeOH was added 15ml concentrated HCl, and then n-butylnitrite (19.5ml, 0.17mol) in 50ml MeOH at 400C. The solution was stirred for 2 hours during which time a precipitate was formed. The precipitate was collected and dried to yield a white solid (22.3g, 75% yield). LC-MS: 192 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hypochlorite; acetic acid In water at 0 - 17℃; for 3.33333h; | 1 EXAMPLE l; PREPARATION OF 4-CHLORO-5-METHOXYTNDAN-1 -OlSfE; 5-Methoxyindan-l-one (17.5 kg, 108 mol) was dissolved in AcOH (147 kg) and cooled to +14°C. Sodium hypochlorite 10/11% aqueous solution (87 kg, 136 mol) was added such that the internal temperature was maintained below 17°C (2.5 h addition time). After a 20 min age at <10°C, the batch was cooled to 0-20C and aged for 30 min. Water (50 L) was then added to crystallised and the batch. The batch was filtered and the cake washed with 5: 1 water/AcOH (18 L) followed by water (2 x 20 L). Drying at 400C under a N2 sweep afforded 15.57 kg of 4-chloro-5-methoxyindan-l-one as an off- white solid in 74% yield. 1H NMR (400 MHz, CDCl3) δ 7.66 (IH, d, J= 8.4 Hz), 7.00 (IH, d, J= 8.4 Hz), 4.00 (3H, s), 3.09 (2H, t, J= 6.0 Hz), 2.71. (2H, d, J= 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 204.8, 160.0, 154.7, 131.4, 123.3, 119.7, 111.5, 56.7, 36.3, 24.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3h; Irradiation; | |
80% | Stage #1: 5-methoxy-1-indanone With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3h; Reflux; Irradiation; Stage #2: With triethylamine In tetrachloromethane at 20℃; for 16h; | 128.1 To the resulting solution, NBS (3.14g, 17.62mmol) and AIBN (394mg, 2.40mmol) were added. The resulting mixture was allowed to reflux for 3 h, while being irradiated by a tungsten lamp (375W). After cooling to room temperature, triethylamine (4.05g, 40.05mmol) was added and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. Na2S203 extracted with CH2Cl2(20mLx3). The organic layers were washed H20 and brine, dried over MgS04 and concentrated in vacuo to give the desired product (1.55g, 80%). NMR (300MHz, CDC13) δ 3.89(s, 3H), 6.21(s, 1H), 6.71 (dd, 1H, J= 2.0, 8.0Hz), 6.77(d, 1H, J= 2.0Hz), 7.38(d, 1H J= 8.0H); MS(m/e, M+) : 239 |
80% | Stage #1: 5-methoxy-1-indanone With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3h; Reflux; Irradiation by tungsten lamp; Stage #2: With triethylamine In tetrachloromethane at 20℃; for 16h; | 128.1 Step 1. 3-Bromo-5-methoxy-1H-inden-1-one 5-Methoxy-1H-indan-1-one (1.3 g, 8.01 mmol) was placed into a flask and dissolved in CCl4 (10 mL). To the resulting solution, NBS (3.14 g, 17.62 mmol) and AIBN (394 mg, 2.40 mmol) were added. The resulting mixture was allowed to reflux for 3 h, while being irradiated by a tungsten lamp (375W). After cooling to room temperature, triethylamine (4.05 g, 40.05 mmol) was added and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. Na2S2O3 extracted with CH2Cl2(20 mLx3). The organic layers were washed H2O and brine, dried over MgSO4 and concentrated in vacuo to give the desired product (1.55 g, 80%). 1H NMR (300 MHz, CDCl3) δ 3.89 (s, 3H), 6.21 (s, 1H), 6.71 (dd, 1H, J=2.0, 8.0 Hz), 6.77 (d, 1H, J=2.0 Hz), 7.38 (d, 1H J=8.0H); MS (m/e, M+): 239 |
Stage #1: 5-methoxy-1-indanone With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2h; Inert atmosphere; Irradiation; Reflux; Stage #2: With triethylamine In tetrachloromethane at 0 - 20℃; for 9h; Inert atmosphere; | Preparation of Starting Materials Synthesis of 3-Aryl-1H-inden-1-ones General procedure: General procedure: 3-Aryl-1H-inden-1-ones 1 were synthesized according to the reported procedure.[1] In a 500 mL round bottomed flask, 1-indanone I (1.0 equiv.) was dissolved in carbon tetrachloride, N-bromosuccinimide (2.0 equiv.) and a catalytic amount of AIBN (0.02 equiv.) were added to the solution. The resulting solution was illuminated using visible light (80 W, 425 nm) under refluxing conditions for 2 h. Following cooling to 0 oC, triethylamine (3.5 equiv.) was added and the reaction mixture was stirred for another 9 h. The solids were removed from the reaction mixture by filtration and washed with carbon tetrachloride. The filtrate was concentrated and then diluted with 50 mL of diethyl ether, and the organic portion was extracted using the solution of 1 N HCl. The organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified with 200-300 mesh silica gel column chromatography (5:1 hexanes/EA) to give the corresponding 3-bromo-1-indenone II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 5-methoxy-1-indanone With zinc In tetrahydrofuran at 60℃; Stage #2: Ethyl bromodifluoroacetate In tetrahydrofuran at 60℃; for 3h; | 12.1 An oven dried 3-necked round-bottomed flask was fitted with a thermometer, a condenser and an addition funnel. Under argon protection, a suspension of 5-methoxy-1- indanone (2.66 g, 16.4 [MMOL)] and Zn powder (Lancaster, 1.87 g, 28.7 [MMOL)] in 100 mL anhydrous THF was stirred at [60C] (internal temperature), while a solution of ethyl [BROMODIFLUOROACETATE] (5.00 g, 24.6 [MMOL)] in 30 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at [60C] (internal temperature) for 3 h. The reaction mixture was cooled in an ice- water bath followed by slow addition of 125 mL of 1 N HCI solution. The pot temperature was maintained [BELOW 20C.] The mixture was then extracted with EtOAc. The organic layer was washed with water until pH 6.0-7. 0, then saturated NaCI solution, and dried over [NA2SO4.] The product (4.6 g, >99%), a yellow oil, was obtained after solvent removal and drying under [VACUUM. 1H] NMR [(CDCI3)] : [B] 7.38 (d, [1] H), 6.79 (m, 2 H), 4.34 (q, 2 H), 3.81 (s, 3 H), 2.93 (m, 4 H), 2.16 (m, [1H),] 1.31 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | R.29.A 5-methoxy-1H-inden-1,2(3H)-dione 2-oxime Step A 5-methoxy-1H-inden-1,2(3H)-dione 2-oxime Using 5-methoxyindan-1-one (5.00 g, 30.8 mmol) and according to the method of Reference Example 25, step A, the title compound (5.35 g, yield 91%) was obtained as a bistered solid. 1H-NMR (300 MHz, DMSO-d6); δ(ppm) 3.73 (s, 2H), 3.89 (s, 3H), 7.02 (dd, J=2.1, 8.7, 1H), 7.15 (d, J=1.8, 1H), 7.69 (d, J=8.7, 1H), 12.45 (s, 1H). | |
With hydrogenchloride; n-Butyl nitrite In methanol at 40℃; for 0.5h; | 1 Step 1: (2Z)-5-(methyloxy)-1H-indene-1,2(3H)-dione 2-oxime Preparation To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40 degrees Centigrade was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by concentrated HCl (0.6 mL). The reaction was stirred for 30 min during which time a precipitate formed, collected, dried and used without further purification. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.60 (br.s, 2H) 3.86 (s, 3H) 6.99 (dd, J=8.54, 2.2 Hz, 1H) 7.12 (d, J=1.71 Hz, 1H) 7.66 (d, J=8.55 Hz, 1H) 12.45 (s, 1H) | |
With hydrogenchloride; n-Butyl nitrite In methanol; water at 40℃; for 0.5h; | III-13.1 (2Z)-5-(methyloxy)-1H-indene-1,2(3H)-dione 2-oxime To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40° C. was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by conc HCl (0.6 mL). The reaction was stirred 30 min, precipitated solid was collected by filtration, air-dried and used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of diisopropylamine (5.2 ml_, 36.9 mmol), in THF (20 ml_) is added n-BuLi (14.8 mL, 36.9 mmol, 2.5 M in hexane) at -78 0C. After 30 min, 5-methoxyindan-1-one (5.0 g, 30.8 mmol) in THF (35 mL) is added. After it is stirred at -78 0C for 1 h, the mixture is warmed to 10 0C for 30 min. The mixture is cooled again to -78 0C and methyl iodide (2.3 mL, 36.9 mmol) is added. The mixture is then warmed to RT over 1 h. NH4CI solution is added and extracted with EtOAc. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound (2.38 g): (M+H)+ = 177. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With selenium(IV) oxide; water In 1,4-dioxane at 180℃; for 0.0833333h; Sealed tube; Microwave irradiation; | General experimental procedure for the synthesis of the ninhydrins (2): General procedure: A sealed-pressurised reaction vessel (5mL) equipped with a magnetic stirrer was charged with indan-1-one (1equiv), selenium dioxide (3.1equiv) and dioxane/water (3mL/0.3mL). It was then irradiated in a Biotage Initiator Microwave synthesizer 2.0 440W with microwave heating to 180°C with a maximum of 400W for 5min. Then, the vessel was rapidly forced-air cooled to room temperature. The mixture was transferred into a round bottom flask, and the vessel washed with acetone. Silica was added to prepare a solid deposit. The volatile solvents were then evaporated in vacuo before purification by flash chromatography (ethyl acetate/cyclohexane) to afford the corresponding ninhydrin. |
73% | With selenium(IV) oxide In 1,4-dioxane for 3h; Inert atmosphere; Reflux; | Synthesis of 5-(4,4,4-trifluorobutyloxy)ninhydrin (5a) General procedure: 5-(4,4,4-Trifluorobutyloxy)-1-indanone (4a, 1.800 g, 6.97 mmol) was added to a suspension of selenium dioxide (3.870 g, 34.88 mmol) in dioxane (10 mL). The suspension was stirred for 3 h to reflux under an argon atmosphere, filtered, and the solvents evaporated. The residue was poured into dichloromethane (30 mL) into which the unreacted SeO2 precipitated. The SeO2 was filtered off and the filtrate evaporated to dryness. The crude product was purified by column chromatography (dichloromethane/ethyl acetate 80: 20 % v/v). |
With selenium(IV) oxide In 1,4-dioxane; water at 180℃; for 0.0833333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | General procedure: To a suspension of benzyltriphenylphosphonium bromide (1.63 g, 3.76 mmol) in THF (40 mL) was dropwise added n-BuLi (2.35 mL, 1.6 M in hexanes). After the system was stirred at room temperature for 2 h, indanone (7a, 0.25 g, 1.89 mmol) or its derivative (8a-17a, 1.89 mmol) in THF (10 mL) was added. The reaction mixture was stirred at reflux for 24 h, then, cooled to room temperature, quenched with water (20 mL), and extracted with n-hexane (3 × 30 mL). The organic layers were combined, washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane) to give the corresponding products (7b-17b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: ethyl trifluoroacetate, With sodium methylate In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 5-methoxy-1-indanone In methanol at 0 - 20℃; for 14h; Inert atmosphere; | 4.2. General procedure for the synthesis of diketones 2a-f General procedure: Sodium (1.2 equiv) was reacted with methanol (10.0 equiv) at 0 °C. To this freshly prepared sodium methylate suspension ethyl trifluoroacetate (1.0 equiv) has been added under stirring at 0 °C and stirring was continued for 30 min followed by addition of ketone 1a-f (1.0 equiv). The reaction mixture was stirred for additional 14 h and then was worked up with hydrochloric acid (10%, 50 mL). The organic layer was separated and extracted with diethylether (3×40 mL). The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-heptane/EtOAc 20:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 1,3 dithiane With n-butyllithium In tetrahydrofuran; hexanes at -15℃; for 1h; Stage #2: 5-methoxy-1-indanone In tetrahydrofuran; hexanes at -15 - 20℃; for 4h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; | 7a A solution of 1,3-dithiane (2.37 g, 19.7 mmol) in tetrahydrofuran (30 mL) was cooled to -15 0C and n-butyl lithium (2.5 M in hexanes, 7.40 mL, 18.5 mmol) was added. After stirring at -15 0C for 1 h, 5-(methyloxy)-2,3-dihydro-lH-inden-l-one (2.0 g, 12.3 mmol) in tetrahydrofuran (75 mL) was added dropwise, then the mixture was allowed to warm to room temperature over 4 h. Ethyl acetate was added and the mixture was washed with water and brine, then dried over sodium sulfate and concentrated. The residue was taken up in toluene (75mL) and/?αra-toluenesulfonic acid (350 mg, 1.85 mmol) was added. The mixture was heated at reflux in a Dean Stark apparatus for 2 h, then filtered through a plug of Celite, and concentrated. The residue was purified by silica gel chromatography eluting with 1 :4 ethyl acetate: hexanes to give 2.24 g (69%) of a viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hypochlorite; acetic acid In water at 0 - 17℃; for 3.33333h; Large scale; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | General procedure: A solution of the 2.5 mmol of the appropriate acetophenone, indanone, tetralone derivative or 1,3-diacteylbenzene and 2mL 50% NaOH in 10mL ethanol was stirred at room temperature for 30min. Then, 2.5mmol (or 5mmol with 1,3-diacetylbenzene) of the corresponding benzaldehyde or cinnamaldehyde derivative, dissolved in 1mL ethanol, were added and stirred at room temperature After conversion of the starting compounds was completed as monitored by TLC, the reaction mixture was poured into ice water and acidified with 10% HCl to pH 6. The so-formed solid was filtered off and the crude product was further purified by recrystallization in ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | To a solution of 5-methoxy-1-indanone (0.32 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (0.36 g, 2 mmol) in toluene (30 mL) was added p-toluenesulfonic acid (0.45 g, 2.4 mmol). After heated atreflux using a Dean-Stark for 4h, the mixture was cooled to room temperature and the solvent was removed in vacuum, then 5% sodium bicarbonate solution was added until pH 8. After extraction with dichloromethane (4x), the organic layer was dried over magnesium sulfate and concentrated to dryness. The residue was taken up with EtOAc and the solid was filtered, rinsed with EtOAc to afford the title compound 91 as a yellow solid (Yield 330 mg, 50%).1fl NMR (300 MHz, CDC13, 6): 3.91 (br s, 5H), 6.96-7.00 (m, 2H), 7.49 (d, 1H, J 5,1 Hz), 7.74(t, 1H, J= 2.4 Hz), 7.87 (d, 1H, J= 8.4 Hz), 8.58 (d, 1H, J= 5.1 Hz), 8.82 (s, 1H).?3C NMR (75 MHz, CDCI3, 6): 31.7, 55.8, 109.8, 115.8, 123,5, 126.7, 128.2, 131.1, 141.2, 143.1, 148.3, 152.3, 153.0, 165.8, 191.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydride In toluene; mineral oil at 100℃; Inert atmosphere; | 244.1 Step 1: Ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate Step 1: Ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1 g, 46.00 mmol, 2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-1H-inden-1-one (3 g, 18.50 mmol, 1.00 equiv) at 30° C. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3*100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2*20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate as yellow oil. |
47% | With sodium hydride In toluene at 30 - 100℃; Inert atmosphere; | 244.1 Step 1: Ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1 g, 46.00 mmol, 2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-1H-inden-1-one (3 g, 18.50 mmol, 1.00 equiv) at 30° C. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3*100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2*20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate as yellow oil. |
47% | With sodium hydride In toluene at 100℃; Inert atmosphere; | 244.1 Step 1; Ethyl 2-[(lE)-5-methoxy-2, 3-dihydro-lH-inden-l-ylidenelacetate Into a 250-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (lg, 46.00 mmol,2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-lH-inden-l-one (3 g, 18.50 mmol, 1.00 equiv) at 30°C. The resulting solution was stirred overnight at 100°C in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3x100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2x20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(lE)-5- methoxy-2,3-dihydro-lH-inden-l-ylidene]acetate as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | With sodium hydroxide In ethanol | 5.5. Synthesis of (E)-1-substitutedphenyl-3-(3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-yl)prop-2-en-1-one 17(a-f) General procedure: To the 3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carbaldehyde (12a) prepared in the above step was addeddifferent ketones and catalytic amount of sodium hydroxide(1.0 ml) in ethanol. The reaction mixture was heated to reflux for1-2 h at 85 °C. Completion of the reaction was determined by TLCfollowed by extracted the crude compounds with ethyl acetatethrice and combined organic layers dried on anhydrous sodiumsulphate. The crude compounds were purified by means of columnchromatography using ethyl acetate and hexane as solvent systemto provide pure compounds of 17a-f in good yields. |
67.4% | With sodium hydroxide In ethanol at 35℃; for 2h; | 8 Example 8 (E)-5-methoxy-2-((3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol-5-yl)methylene)-2,3- dihydro-1H-inden-1 -one (23e) Example 8(E)-5-methoxy-2-((3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol-5-yl)methylene)-2,3- dihydro-1H-inden-1 -one (23e)5-methoxy-2,3-dihydro-1H-inden-l-one (r) (162 mg, 1.0 mmol) was added to 3-(3,4,5- trimethoxyphenyl)-1H-pyrazole-5-carbaldehyde (5e) (262 mg, 1.0 mmol) in ethanol (10 mL) and catalytic amount (5 mg) of sodium hydroxide (NaOH) to obtain a reactionmixture. The reaction mixture was stirred at 35°C for 2 h and the reaction was monitored by TLC using ethyl acetate/hexane (4:6) as a solvent system. This solution was then evaporated by vacuum distillation and the residue was neutralized with dii. HCI solution which was further extracted with ethyl acetate (25 mL x 4). The organic solution was dried over anhydrous Na2SO4 and the solvent was evaporated to obtain acrude product. The crude product was further purified by column chromatography using ethyl acetate/hexane (4:6) as eluent to obtain the pure compound 23e (274 mg, 67.4%yield).‘H NMR (CDC13): 8 1.25 (s, 2H), 2.36 (s, 3H), 3.94 (s, 6H), 4.01 (s, 3H), 6.80 (s, 1H), 6.91-6.99 (m, IH), 7.07 (s, 2H) 7.57(d, 2H, J 8.4 Hz) ppm; FABMS :407M+H)4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In toluene; at 120℃; for 6h; | A solution of 180 (100 mg, 0.617 mmol) in toluene 15 ml was added 66 (151.2 mg, 0.864 mmol). PTSA (234.5 mg, 1.234 mmol) was added to the reaction mass. The reaction was stirred at 120 C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 183, used the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With manganese(IV) oxide; oxygen In chlorobenzene at 100℃; for 4h; Autoclave; | 27 General procedure: 0.01 g of MnO2 catalyst, 0.5 mmol of 1-indanone, 2 mmol of aniline and 2 g of chlorobenzene were added to a stainless steel autoclave with a polytetrafluoroethylene liner.The temperature was raised to 100 ° C by the automatic temperature control program, 0.6MPa oxygen was added and the reaction was carried out for 4 hours. The pressure was kept constant during the reaction.The reaction product was analyzed using GC-MS, N-phenyl phthalimide in 85% yield. The catalyst activity was evaluated in the same manner as in Example 1 except that the amount of the aromatic ketone substrate and the solvent was different.The reaction conditions and the results of the catalytic reaction are shown in Table 2.Different aromatic ring-substituted aromatic ketones and aniline can produce the corresponding N-substituted imides. |
86 %Chromat. | With copper(I) oxide; oxygen In dimethyl sulfoxide at 120℃; for 12h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium hydroxide In methanol at 20℃; | General procedure for preparation of compounds 6a-d General procedure: Commercially available 1-indanone or 5-methoxy-1-indanone (2 mmol) and the appropriatebenzaldehyde (2 mmol) were suspended in methanol (5 mL) containing KOH (4.7%). The reactionwas stirred at room temperature for 2-4 h. The reaction progress was monitored using silica gel TLCwith petroleum ether:ethyl acetate (2:1) serving as mobile phase. Upon completion, cold water (20mL) was added. The resulting precipitate was collected by filtration and the crude thus obtained waspurified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. 4.1.1.4.1. 2-(4-(4-Methylpiperazin-1-yl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (15). Yield: 90%. Mp: 184.7 °C. IR (ATR)Vmax (cm-1): 1678 (CO stretching), 1597-1487 (CC stretching),1222 (C-N stretching), 1103 (C-O stretching), 810 (1,4-disubstituedbenzene out of plane bending). 1H NMR (500 MHz) (DMSO-d6)δ (ppm): 2.23 (3H, s, -N-CH3), 2.44-2.46 (4H, m, H3"H5"),3.29-3.33 (4H, m, H2"H6"), 3.89 (3H, s, -OCH3), 4.01 (2H, s, H3),7.01-7.04 (3H, m, H3'H5'H6), 7.19 (1H, s, H4), 7.38 (1H, s, CH-),7.62 (2H, d, J 8.85 Hz, H2'H6'), 7.70 (1H, d, J 8.50 Hz, H7). 13CAPTNMR (125 MHz) (DMSO-d6) δ (ppm): 32.62 (1C, C3), 46.21 (1C,-N-CH3), 47.33 (2C, C3"C5"), 54.83 (2C, C2"C6"), 56.22 (1C, C5-OCH3), 110.65 (1C, C6), 114.95 (2C, C3'C5'), 115.63 (1C, C4), 125.12(1C, C1'), 125.56 (1C, C7), 131.53 (1C, C7a), 131.86 (1C, C4'), 132.57(1C, CH-), 132.67 (2C, C2'C6'), 151.98 (1C, C2), 152.97 (1C, C3a),165.01 (1C, C5), 193.35 (1C, C1). HRMS (ESI) (M+H+) (m/z): ForC22H24N2O2 Calculated: 349.1911. Found: 349.1911. Elemental analyses:C22H24N2O2, Calculated (%): C, 75.83; H, 6.94; N, 8.04. Found(%): C, 75.82; H, 6.93; N, 8.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium hydroxide; In methanol; at 20℃; for 48h; | General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 1-bromo-3,4,5-trimethoxybenzene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 5-methoxy-1-indanone In tetrahydrofuran at -78 - 20℃; for 12h; Inert atmosphere; | |
75% | Stage #1: 1-bromo-3,4,5-trimethoxybenzene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: 5-methoxy-1-indanone In tetrahydrofuran at -78 - 20℃; for 12h; | 5-Methoxy-1-(3',4',5'-trimethoxyphenyl)-2,3-dihydro-1H-inden-1-ol (26) (WO01/68654). 5-Bromo-1,2,3-trimethoxybenzene (1.95 g, 7.91 mmol) was dissolved in THF (50 mL), and the mixture was cooled to -78° C. n-BuLi (3.3 mL, 8.3 mmol) was added dropwise, and the reaction mixture was stirred for 1 h. Ketone 12 (0.95 g, 5.86 mmol) was dissolved in THF (10 mL) and added dropwise to the reaction flask, and the mixture was stirred for 12 h warming to room temperature, at which time it was washed with water, extracted with EtOAc (3*30 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography using a prepacked 100 g silica column [solvent A: EtOAc; solvent B: hexane; gradient: 10% A/90% B (1 CV), 10% A/90% B→80% A/20% B (10 CV), 80% A/20% B (2 CV); flow rate: 50 mL/min; monitored at 254 nm and 280 nm] to afford tertiary alcohol 26 (1.45 g, 4.39 mmol, 75%) as a yellow oil. NMR data was collected after the subsequent step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.2% | With sodium hydroxide In ethanol at 20℃; | 5.6. Synthesis of (E)-1-substitutedphenyl-3-(3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-yl)prop-2-en-1-one 18(a-f) General procedure: To the 3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazole-5-carbaldehyde (12b) prepared in the previous step was added correspondingsubstituted acetophenones and catalytic amount ofsodium hydroxide in ethanol. The reaction mixture was stirred atroom temperature for 3-4 h and progress of the reaction wasmonitored by TLC. After completion, ethanol was evopouratedunder vacuum and the residue was neutralised with dilute HClsolution. Finally the chalcones were extracted with ethyl acetatefollowed by purification was done by using column chromatographyto obtain pure compounds of 18a-f with good yields(60-75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With manganese(IV) oxide; ammonium hydroxide; oxygen; chlorobenzene; In N,N-dimethyl-formamide; at 100℃; under 15001.5 Torr; for 24h;Autoclave; Green chemistry; | General procedure: 0.01g of MnO2 catalyst, 0.5mmol of 1-indanone, 0.2g of ammonia water (25wt%) and 2g of chlorobenzene were added to a stainless steel autoclave with a polytetrafluoroethylene inner liner.The temperature was raised to 110 by automatic temperature controller, 0.6MPa oxygen was added and the reaction was continued for 4h. The pressure was kept constant during the reaction.The reaction product was analyzed using GC-MS with a phthalamide yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydroxide In ethanol; water at 20℃; for 0.5h; | 5.6 Synthesis of 2-benzylidene-1-indanone derivatives 3a-f [31] A water solution of sodium hydroxide (1.5 eq) was added at room temperature to an ethanol solution of th appropriately commercially available indanones (1 eq) and 4-(3-(piperidin-1-yl)-propoxy)-benzaldehyde (1 eq). The work up was performed as described for compounds 2a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydroxide In ethanol for 4h; | (E)-2-(2-Bromobenzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one(9) To a solution of compound 7(162 mg, 1.00 mmol) in EtOH (15 mL) was added compound 8 (185 mg, 1.00mmol) in EtOH (5 mL) and NaOH (2.5 M, 8 mL) at room temperature. The reaction mixturewas stirred for 4 h, neutralized with 1 M HCl, and extracted with CHCl3(3 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure. The crude product was purifiedby flash column chromatography using 10% ethyl acetate in hexane to yield 9(89%) as off-white solid. Mp 140-141°C. FTIR (n, cm-1): 1694(C=O), 1672 (C=C), 964 (C=C-H). 1H NMR (400 MHz, CDCl3) &120575; 3.37 (s, 2H), 3.82 (s, 3H), 7.03 (dd, 1H, J = 8.4, 2,8 Hz),7.10 (d, 1H, J = 8.4 Hz), 7.16-7.18 (m, 1H), 7.26-7.28 (m, 1H),7.29-7.31 (m, 1H), 7.60-7.62 (m, 1H), 7.80 (s, 1H). 13C NMR (100MHz, CDCl3) &120575; 38.7, 55.2, 110.1, 121.3, 124.6, 126.8, 129.3, 129.5, 130.2, 132.6,133.7, 135.2, 135.8, 136.0, 136.6, 158.4, 187.1. HRMS (EI): calcd for C17H13BrO2[M]+, 328.0098; found, 328.0094. |
With sodium methylate In methanol at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis(1,5-cyclooctadiene)nickel (0); water; [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene at 130℃; for 2h; Neutral conditions; regioselective reaction; | |
46% | With bis(1,5-cyclooctadiene)nickel (0) In water at 130℃; for 2h; Glovebox; Sealed tube; | 25 Example 25: Transfer a 4 mL high temperature pretreated vial with a stir bar into the glove box. To this vial were added Ni (COD) 2 (5.5 mg, 10 mol%), IMes (6.1 mg, 10 mol%), and 0.4 mL of CPME in this order. The mixture was stirred for 5 minutes. Then 1a (0.2 mmol) and 2a (3 eq, 0.6 mmol) were added, followed by H 2 O (3.6 μl, 0.2 mmol). The vial was tightly capped, removed from the glove box and heated at 130 ° C for 2 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column (2-4 cm) to remove metal ions. The solvent was removed by rotary evaporation under reduced pressure, and the crude product was separated by column chromatography (silica gel, PE / Et2O = 200: 1 to 100: 1) to obtain a pure product. The product was a colorless liquid with a yield of 46% and Rf = 0.65 (PE: Et2O = 20: 1) .dr: 1.3: 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogenchloride; In methanol; water; at 60 - 80℃; for 6h; | General procedure: To a solution of (7) 1-(<strong>[4649-09-6]1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> (0.300g, 2.053mmol) in 32% aqueous HCl/methanol (1.5:1 v/v) (4.5ml/3 ml) was added a selected bicyclic scaffold (tetralone, indanone, 3-coumaranone, 4-chromanone and thiochroman-4-one) (2.053mmol) and the reaction was refluxed for at least 6h at 60-80C. The progress of the reaction was monitored by silica gel TLC with ethyl acetate as mobile phase. When the reaction reached completion, the target products were isolated by precipitation with ice-cold water, after which they were purified by recrystallisation with ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium <i>tert</i>-butylate; ammonium chloride; ethanolamine; Selectfluor In water at 120℃; for 24h; Sealed tube; Green chemistry; | |
85% | With potassium <i>tert</i>-butylate; ammonium chloride; ethanolamine; Selectfluor In water at 120℃; for 24h; | 8 Example 8 Preparation of 2,8-dimethoxy-10,12-dihydrodiindeno[1,2-b:2',1'-e]pyridine The first step: add 5-methoxy-1-indanone (32.4mg, 0.2mmol) to a 50mL reaction tube with a ground branch pipe,NH4Cl (53.5mg, 1.0mmol), fluorine reagent (70.9mg, 0.2mmol), potassium tert-butoxide (22.4mg, 0.2mmol),Ethanolamine (1 mL) and water (2 mL).The second step: replace the air in the reaction tube with carbon dioxide gas at one atmospheric pressure, heat to 120°C and stir for 24 hours.The third step: cooling to room temperature, adding 5 mL of water to dilute the reaction solution, extracting the aqueous phase three times with 10 mL dichloromethane, and mixing the dichloromethane phases obtained by the three extractions and draining.The remaining crude product was separated by column chromatography (petroleum ether/ethyl acetate=7:1) to obtain a white solid product (Product 8) in 85% yield. |
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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